Faculty Profiles - YOSHIMURA, Takashi

Synthesis and preclinical testing of a selective beta-subtype agonist of thyroid hormone receptor ZTA-261

Masakazu Nambo, Taeko Nishiwaki-Ohkawa, Akihiro Ito, Zachary T. Ariki, Yuka Ito, Yuuki Kato, Muhammad Yar, Jacky C. -H. Yim, Emily Kim, Elizabeth Sharkey, Keiko Kano, Emi Mishiro-Sato, Kosuke Okimura, Michiyo Maruyama, Wataru Ota, Yuko Furukawa, Tomoya Nakayama, Misato Kobayashi, Fumihiko Horio, Ayato Sato, Cathleen M. Crudden, Takashi Yoshimura

Communications Medicine Vol. 4 ( 1 ) 2024.8

Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media LLC

Abstract

Background

Thyroid hormones (TH) regulate the basal metabolic rate through their receptors THRα and THRβ. TH activates lipid metabolism via THRβ, however, an excess amount of TH can lead to tachycardia, bone loss, and muscle wasting through THRα. In recent years, TH analogs that selectively bind to THRβ have gained attention as new agents for treating dyslipidemia and obesity, which continue to pose major challenges to public health worldwide.

Methods

We developed a TH analog, ZTA-261, by modifying the existing THRβ-selective agonists GC-1 and GC-24. To determine the THRβ-selectivity of ZTA-261, an in vitro radiolabeled TH displacement assay was conducted. ZTA-261 was intraperitoneally injected into a mouse model of high-fat diet-induced obesity, and its effectiveness in reducing body weight and visceral fat, and improving lipid metabolism was assessed. In addition, its toxicity in the liver, heart, and bone was evaluated.

Results

ZTA-261 is more selective towards THRβ than GC-1. Although ZTA-261 is less effective in reducing body weight and visceral fat than GC-1, it is as effective as GC-1 in reducing the levels of serum and liver lipids. These effects are mediated by the same pathway as that of T3, a natural TH, as evidenced by similar changes in the expression of TH-induced and lipid metabolism-related genes. The bone, cardiac, and hepatotoxicity of ZTA-261 are significantly lower than those of GC-1.

Conclusions

ZTA-261, a highly selective and less toxic THRβ agonist, has the potential to be used as a drug for treating diseases related to lipid metabolism.

DOI： 10.1038/s43856-024-00574-z

STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179 Reviewed

Other Link： https://www.nature.com/articles/s43856-024-00574-z

Helmut Grasberger, Alexandra M. Dumitrescu, Xiao-Hui Liao, Elliott G. Swanson, Roy E. Weiss, Panudda Srichomkwun, Theodora Pappa, Junfeng Chen, Takashi Yoshimura, Phillip Hoffmann, Monica Malheiros França, Rebecca Tagett, Kazumichi Onigata, Sabine Costagliola, Jane Ranchalis, Mitchell R. Vollger, Andrew B. Stergachis, Jessica X. Chong, Michael J. Bamshad, Guillaume Smits, Gilbert Vassart, Samuel Refetoff

Nature Genetics Vol. 56 ( 5 ) page： 877 - 888 2024.5

FcRY is a key molecule controlling maternal blook IgY transfer to yolks during egg development in avian species Reviewed Open Access

Okamoto M, Sasaki R, Ikeda K, Doi K, Tatsumi F, Oshima K, Kojima T, Mizushima S, Ikegami K, Yoshimura T, Furukawa K, Kobayashi M, Horio F, Murai A

Frontiers in Immunology Vol. 15 page： 1305587 2024

A transcriptional program underlying the circannual rhythms of gonadal development in medaka Open Access

Tomoya Nakayama, Miki Tanikawa, Yuki Okushi, Thoma Itoh, Tsuyoshi Shimmura, Michiyo Maruyama, Taiki Yamaguchi, Akiko Matsumiya, Ai Shinomiya, Ying-Jey Guh, Junfeng Chen, Kiyoshi Naruse, Hiroshi Kudoh, Yohei Kondo, Honda Naoki, Kazuhiro Aoki, Atsushi J. Nagano, Takashi Yoshimura

Proceedings of the National Academy of Sciences Vol. 120 ( 52 ) 2023.12

Publishing type：Research paper (scientific journal) Publisher：Proceedings of the National Academy of Sciences

To cope with seasonal environmental changes, organisms have evolved approximately 1-y endogenous circannual clocks. These circannual clocks regulate various physiological properties and behaviors such as reproduction, hibernation, migration, and molting, thus providing organisms with adaptive advantages. Although several hypotheses have been proposed, the genes that regulate circannual rhythms and the underlying mechanisms controlling long-term circannual clocks remain unknown in any organism. Here, we show a transcriptional program underlying the circannual clock in medaka fish ( Oryzias latipes ). We monitored the seasonal reproductive rhythms of medaka kept under natural outdoor conditions for 2 y. Linear regression analysis suggested that seasonal changes in reproductive activity were predominantly determined by an endogenous program. Medaka hypothalamic and pituitary transcriptomes were obtained monthly over 2 y and daily on all equinoxes and solstices. Analysis identified 3,341 seasonally oscillating genes and 1,381 daily oscillating genes. We then examined the existence of circannual rhythms in medaka via maintaining them under constant photoperiodic conditions. Medaka exhibited approximately 6-mo free-running circannual rhythms under constant conditions, and monthly transcriptomes under constant conditions identified 518 circannual genes. Gene ontology analysis of circannual genes highlighted the enrichment of genes related to cell proliferation and differentiation. Altogether, our findings support the “histogenesis hypothesis” that postulates the involvement of tissue remodeling in circannual time-keeping.

DOI： 10.1073/pnas.2313514120

Variation in responses to photoperiods and temperatures in Japanese medaka from different latitudes Open Access

Shinomiya A., Adachi D., Shimmura T., Tanikawa M., Hiramatsu N., Ijiri S., Naruse K., Sakaizumi M., Yoshimura T.

Zoological Letters Vol. 9 ( 1 ) 2023.12

Publisher：Zoological Letters

Seasonal changes are more robust and dynamic at higher latitudes than at lower latitudes, and animals sense seasonal changes in the environment and alter their physiology and behavior to better adapt to harsh winter conditions. However, the genetic basis for sensing seasonal changes, including the photoperiod and temperature, remains unclear. Medaka (Oryzias latipes species complex), widely distributed from subtropical to cool-temperate regions throughout the Japanese archipelago, provides an excellent model to tackle this subject. In this study, we examined the critical photoperiods and critical temperatures required for seasonal gonadal development in female medaka from local populations at various latitudes. Intraspecific differences in critical photoperiods and temperatures were detected, demonstrating that these differences were genetically controlled. Most medaka populations could perceive the difference between photoperiods for at least 1 h. Populations in the Northern Japanese group required 14 h of light in a 24 h photoperiod to develop their ovaries, whereas ovaries from the Southern Japanese group developed under 13 h of light. Additionally, Miyazaki and Ginoza populations from lower latitudes were able to spawn under short-day conditions of 11 and 10 h of light, respectively. Investigation of the critical temperature demonstrated that the Higashidori population, the population from the northernmost region of medaka habitats, had a critical temperature of over 18 °C, which was the highest critical temperature among the populations examined. The Miyazaki and the Ginoza populations, in contrast, were found to have critical temperatures under 14 °C. When we conducted a transplant experiment in a high-latitudinal environment using medaka populations with different seasonal responses, the population from higher latitudes, which had a longer critical photoperiod and a higher critical temperature, showed a slower reproductive onset but quickly reached a peak of ovarian size. The current findings show that low latitudinal populations are less responsive to photoperiodic and temperature changes, implying that variations in this responsiveness can alter seasonal timing of reproduction and change fitness to natural environments with varying harshnesses of seasonal changes. Local medaka populations will contribute to elucidating the genetic basis of seasonal time perception and adaptation to environmental changes.

DOI： 10.1186/s40851-023-00215-8

Orphan nuclear receptor nr4a1 regulates winter depression-like behavior in medaka Open Access

Nakayama T., Hirano F., Okushi Y., Matsuura K., Ohashi M., Matsumiya A., Yoshimura T.

Neuroscience Letters Vol. 814 2023.9

Publisher：Neuroscience Letters

About 10% of the population suffers from depression in winter at high latitude. Although it has become a serious public health issue, its underlying mechanism remains unknown and new treatments and therapies are required. As an adaptive strategy, many animals also exhibit depression-like behavior in winter. Previously, it has been reported that celastrol, a traditional Chinese medicine, can rescue winter depression-like behavior in medaka, an excellent model of winter depression. Nuclear receptor subfamily 4 group A member 1 (nr4a1, also known as nur77) is a known target of celastrol, and the signaling pathway of nr4a1 was suggested to be inactive in medaka brain during winter, implying the association of nr4a1 and winter depression-like behavior. However, the direct evidence for its involvement in winter depression-like behavior remains unclear. The present study found that nr4a1 was suppressed in the medaka brain under winter conditions. Cytosporone B, nr4a1 chemical activator, reversed winter depression-like behavior under winter conditions. Additionally, nr4a1 mutant fish generated by CRISPR/Cas9 system showed decreased sociability under summer conditions. Therefore, our results demonstrate that the seasonal regulation of nr4a1 regulates winter depression-like behavior and offers potential therapeutic target.

DOI： 10.1016/j.neulet.2023.137469

Mimicking seasonal changes in light-dark cycle and ambient temperature modulates gut microbiome in mice under the same dietary regimen Reviewed

Matsumoto S, Ren L, Iigo M, Murai A, Yoshimura T

PLoS One Vol. 18 page： e0278013 2023.2

Novel hypnotics of Japanese traditional herbal medicines to caffeine-induced insomnia in Drosophila by using Newly-developed automated sleep and rhythm analysis system (AutoCircaS) Reviewed Open Access

Inoue E, Suzuki T, Nakayama T, Yoshimura T, Sudo K, Shimizu Y, Iwaki Y, Kawasaki H, Ishida N

Gene Vol. 846 page： 146852 2022.12

Real time monitoring of cold Ca2+ dependent transcription and its modulation by NCX inhibitors Reviewed Open Access

Wang HT, Miyairi S, Kitamura M, Iizuka K, AsanoY, Yoshimura T, Kon N

Scientific Reports Vol. 12 ( 1 ) page： 17325 2022.12

Level of constitutively expressed BMAL1 affects the robustness of circadian oscillations Open Access

Padlom A., Ono D., Hamashima R., Furukawa Y., Yoshimura T., Nishiwaki-Ohkawa T.

Scientific Reports Vol. 12 ( 1 ) 2022.12

Publisher：Scientific Reports

The circadian rhythm is a biological oscillation of physiological activities with a period of approximately 24 h, that is driven by a cell-autonomous oscillator called the circadian clock. The current model of the mammalian circadian clock is based on a transcriptional-translational negative feedback loop in which the protein products of clock genes accumulate in a circadian manner and repress their own transcription. However, several studies have revealed that constitutively expressed clock genes can maintain circadian oscillations. To understand the underlying mechanism, we expressed Bmal1 in Bmal1-disrupted cells using a doxycycline-inducible promoter and monitored Bmal1 and Per2 promoter activity using luciferase reporters. Although the levels of BMAL1 and other clock proteins, REV-ERBα and CLOCK, showed no obvious rhythmicity, robust circadian oscillation in Bmal1 and Per2 promoter activities with the correct phase relationship was observed, which proceeded in a doxycycline-concentration-dependent manner. We applied transient response analysis to the Bmal1 promoter activity in the presence of various doxycycline concentrations. Based on the obtained transfer functions, we suggest that, at least in our experimental system, BMAL1 is not directly involved in the oscillatory process, but modulates the oscillation robustness by regulating basal clock gene promoter activity.

DOI： 10.1038/s41598-022-24188-4

Prostaglandin E2 synchronizes lunar-regulated beach spawning in grass puffers Reviewed Open Access

Junfeng Chen, Yuma Katada, Kousuke Okimura, Taiki Yamaguchi, Ying-Jey Guh, Tomoya Nakayama, Michiyo Maruyama, Yuko Furukawa, Yusuke Nakane, Naoyuki Yamamoto, Yoshikatsu Sato, Hironori Ando, Asako Sugimura, Kazufumi Tabata, Ayato Sato, Takashi Yoshimura

Current Biology Vol. 32 ( 22 ) page： 4881 - 4889.e5 2022.10

Adenylate kinase 1 overexpression increases locomotor activity in medaka fish Reviewed Open Access

Maruyama M, Furukawa Y, Kinoshita M, Mukaiyama A, Akiyama S, Yoshimura T

PLOS ONE Vol. 17 ( 1 January ) page： e0257967 2022.1

Modulation of circadian clock by crude drug extracts used in Japanese Kampo medicine. Reviewed International journal Open Access

Manhui Zhang, Kohei Kobayashi, Haruki Atsumi, Yuma Katada, Yusuke Nakane, Junfeng Chen, Ryo Nagano, Naoya Kadofusa, Taeko Nishiwaki-Ohkawa, Naohiro Kon, Tsuyoshi Hirota, Ayato Sato, Toshiaki Makino, Takashi Yoshimura

Scientific reports Vol. 11 ( 1 ) page： 21038 - 21038 2021.10

Language：English Publishing type：Research paper (scientific journal)

Circadian rhythm is an approximately 24 h endogenous biological rhythm. Chronic disruption of the circadian clock leads to an increased risk of diabetes, cardiovascular disease, and cancer. Hence, it is important to develop circadian clock modulators. Natural organisms are a good source of several medicines currently in use. Crude drugs used in Japanese traditional Kampo medicine or folk medicines are an excellent source for drug discovery. Furthermore, identifying new functions for existing drugs, known as the drug repositioning approach, is a popular and powerful tool. In this study, we screened 137 crude drug extracts to act as circadian clock modulators in human U2OS cells stably expressing the clock reporter Bmal1-dLuc, and approximately 12% of these modulated the circadian rhythm. We further examined the effects of several crude drugs in Rat-1 fibroblasts stably expressing Per2-luc, explant culture of lung from Per2::Luciferase knockin mice, and zebrafish larvae in vivo. Notably, more than half of the major ingredients of these crude drugs were reported to target AKT and its relevant signaling pathways. As expected, analysis of the major ingredients targeting AKT signaling confirmed the circadian clock-modulating effects. Furthermore, activator and inhibitor of AKT, and triple knockdown of AKT isoforms by siRNA also modulated the circadian rhythm. This study, by employing the drug repositioning approach, shows that Kampo medicines are a useful source for the identification of underlying mechanisms of circadian clock modulators and could potentially be used in the treatment of circadian clock disruption.

DOI： 10.1038/s41598-021-00499-w

Effects of Cryptochrome-modulating compounds on circadian behavioral rhythms in zebrafish. Reviewed International journal Open Access

Mui Iida, Yusuke Nakane, Takashi Yoshimura, Tsuyoshi Hirota

Journal of biochemistry Vol. 171 ( 5 ) page： 501 - 507 2021.9

Language：English Publishing type：Research paper (scientific journal)

The circadian clock controls daily rhythms of various physiological processes, and impairment of its function causes many diseases including sleep disorders. Chemical compounds that regulate clock function are expected to be applied for treatment of circadian clock-related diseases. We previously identified small-molecule compounds KL001, KL101, and TH301 that lengthen the period of cellular circadian clock by directly targeting clock proteins Cryptochromes (CRYs) in mammals. KL001 targets both CRY1 and CRY2 isoforms, while KL101 and TH301 are isoform-selective compounds and require CRY C-terminal region for their effects. For further application of these compounds, the effects on locomotor activity rhythms at the organismal level need to be investigated. Here we used zebrafish larvae as an in vivo model system and found that KL001 lengthened the period of locomotor activity rhythms in a dose-dependent manner. In contrast, KL101 and TH301 showed no effect on the period. The amino acid sequences of CRY C-terminal regions are diverged in zebrafish and mammals, supporting the importance of this region for the effects of KL101 and TH301. This study demonstrated efficacy of CRY modulation for controlling circadian behavioral rhythms in organisms and suggested species-dependent differences in the effects of isoform-selective CRY-modulating compounds.

DOI： 10.1093/jb/mvab096

ケミカルゲノミクスで明らかにするメダカの冬季うつ様行動の分子基盤：冬季うつ病の理解と克服にむけて Invited

沖村光祐，中山友哉，吉村崇

化学と生物 Vol. 59 page： 369 - 376 2021.8

Photoperiodic regulation of dopamine signaling regulates seasonal changes in retinal photosensitivity in mice. Reviewed International journal Open Access

Kousuke Okimura, Yusuke Nakane, Taeko Nishiwaki-Ohkawa, Takashi Yoshimura

Scientific reports Vol. 11 ( 1 ) page： 1843 - 1843 2021.1

Language：English Publishing type：Research paper (scientific journal)

At high latitudes, approximately 10% of people suffer from depression during the winter season, a phenomenon known as seasonal affective disorder (SAD). Shortened photoperiod and/or light intensity during winter season are risk factors for SAD, and bright light therapy is an effective treatment. Interestingly, reduced retinal photosensitivity along with the mood is observed in SAD patients in winter. However, the molecular basis underlying seasonal changes in retinal photosensitivity remains unclear, and pharmacological intervention is required. Here we show photoperiodic regulation of dopamine signaling and improvement of short day-attenuated photosensitivity by its pharmacological intervention in mice. Electroretinograms revealed dynamic seasonal changes in retinal photosensitivity. Transcriptome analysis identified short day-mediated suppression of the Th gene, which encodes tyrosine hydroxylase, a rate-limiting enzyme for dopamine biosynthesis. Furthermore, pharmacological intervention in dopamine signaling through activation of the cAMP signaling pathway rescued short day-attenuated photosensitivity, whereas dopamine receptor antagonists decreased photosensitivity under long-day conditions. Our results reveal molecular basis of seasonal changes in retinal photosensitivity in mammals. In addition, our findings provide important insights into the pathogenesis of SAD and offer potential therapeutic interventions.

DOI： 10.1038/s41598-021-81540-w

Light and Hormones in Seasonal Regulation of Reproduction and Mood Invited Reviewed Open Access

Chen Junfeng, Okimura Kousuke, Yoshimura Takashi

ENDOCRINOLOGY Vol. 161 ( 9 ) 2020.9

Publisher：Endocrinology (United States)

Organisms that inhabit the temperate zone exhibit various seasonal adaptive behaviors, including reproduction, hibernation, molting, and migration. Day length, known as photoperiod, is the most noise-free and widely used environmental cue that enables animals to anticipate the oncoming seasons and adapt their physiologies accordingly. Although less clear, some human traits also exhibit seasonality, such as birthrate, mood, cognitive brain responses, and various diseases. However, the molecular basis for human seasonality is poorly understood. Herein, we first review the underlying mechanisms of seasonal adaptive strategies of animals, including seasonal reproduction and stress responses during the breeding season. We then briefly summarize our recent discovery of signaling pathways involved in the winter depression-like phenotype in medaka fish. We believe that exploring the regulation of seasonal traits in animal models will provide insight into human seasonality and aid in the understanding of human diseases such as seasonal affective disorder (SAD).

DOI： 10.1210/endocr/bqaa130

Artificial selection reveals the role of transcriptional constraints in the maintenance of life history variation Open Access

Genetic analysis of body weight in wild populations of medaka fish from different latitudes. Reviewed International journal Open Access

Tamiris I Yassumoto, Mana Nakatsukasa, Atsushi J Nagano, Masaki Yasugi, Takashi Yoshimura, Ai Shinomiya

PloS one Vol. 15 ( 6 ) page： e0234803 2020.6

Language：English Publishing type：Research paper (scientific journal)

The genetic bases of growth and body weight are of economic and scientific interest, and teleost fish models have proven useful in such investigations. The Oryzias latipes species complex (medaka) is an abundant freshwater fish in Japan and suitable for genetic studies. We compared two wild medaka stocks originating from different latitudes. The Maizuru population from higher latitudes weighed more than the Ginoza population. We investigated the genetic basis of body weight, using quantitative trait locus (QTL) analysis of the F2 offspring of these populations. We detected one statistically significant QTL for body weight on medaka chromosome 4 and identified 12 candidate genes that might be associated with body weight or growth. Nine of these 12 genes had at least one single nucleotide polymorphism that caused amino acid substitutions in protein-coding regions, and we estimated the effects of these substitutions. The present findings might contribute to the marker-assisted selection of economically important aquaculture species.

DOI： 10.1371/journal.pone.0234803

Pick Joel L., Hatakeyama Masaomi, Ihle Kate E., Gasparini Julien, Haussy Claudy, Ishishita Satoshi, Matsuda Yoichi, Yoshimura Takashi, Kanaoka Masahiro M., Shimizu-Inatsugi Rie, Shimizu Kentaro K., Tschirren Barbara

EVOLUTION LETTERS Vol. 4 ( 3 ) page： 200 - 211 2020.6

Language：Japanese Publisher：Evolution Letters

The trade-off between reproduction and self-maintenance is a cornerstone of life history theory, yet its proximate underpinnings are elusive. Here, we used an artificial selection approach to create replicated lines of Japanese quail (Coturnix japonica) that differ genetically in their reproductive investment. Whole transcriptome sequencing revealed that females from lines selected for high reproductive output show a consistent upregulation of genes associated with reproduction but a simultaneous downregulation of immune genes. Concordant phenotypic differences in immune function (i.e., specific antibody response against keyhole limpet hemocyanin) were observed between the selection lines, even in males who do not provide parental care. Our findings demonstrate the key role of obligate transcriptional constraints in the maintenance of life history variation. These constraints set fundamental limits to productivity and health in natural and domestic animal populations.

DOI： 10.1002/evl3.166

Seasonal changes in NRF2 antioxidant pathway regulates winter depression-like behavior. Reviewed International coauthorship International journal Open Access

Tomoya Nakayama, Kousuke Okimura, Jiachen Shen, Ying-Jey Guh, T Katherine Tamai, Akiko Shimada, Souta Minou, Yuki Okushi, Tsuyoshi Shimmura, Yuko Furukawa, Naoya Kadofusa, Ayato Sato, Toshiya Nishimura, Minoru Tanaka, Kei Nakayama, Nobuyuki Shiina, Naoyuki Yamamoto, Andrew S Loudon, Taeko Nishiwaki-Ohkawa, Ai Shinomiya, Toshitaka Nabeshima, Yusuke Nakane, Takashi Yoshimura

Proceedings of the National Academy of Sciences of the United States of America Vol. 117 ( 17 ) page： 9594 - 9603 2020.4

Language：English Publishing type：Research paper (scientific journal)

Seasonal changes in the environment lead to depression-like behaviors in humans and animals. The underlying mechanisms, however, are unknown. We observed decreased sociability and increased anxiety-like behavior in medaka fish exposed to winter-like conditions. Whole brain metabolomic analysis revealed seasonal changes in 68 metabolites, including neurotransmitters and antioxidants associated with depression. Transcriptome analysis identified 3,306 differentially expressed transcripts, including inflammatory markers, melanopsins, and circadian clock genes. Further analyses revealed seasonal changes in multiple signaling pathways implicated in depression, including the nuclear factor erythroid-derived 2-like 2 (NRF2) antioxidant pathway. A broad-spectrum chemical screen revealed that celastrol (a traditional Chinese medicine) uniquely reversed winter behavior. NRF2 is a celastrol target expressed in the habenula (HB), known to play a critical role in the pathophysiology of depression. Another NRF2 chemical activator phenocopied these effects, and an NRF2 mutant showed decreased sociability. Our study provides important insights into winter depression and offers potential therapeutic targets involving NRF2.

DOI： 10.1073/pnas.2000278117

The quail genome: insights into social behaviour, seasonal biology and infectious disease response Reviewed Open Access

Morris Katrina M., Hindle Matthew M., Boitard Simon, Burt David W., Danner Angela F., Eory Lel, Forrest Heather L., Gourichon David, Gros Jerome, Hillier LaDeana W., Jaffredo Thierry, Khoury Hanane, Lansford Rusty, Leterrier Christine, Loudon Andrew, Mason Andrew S., Meddle Simone L., Minvielle Francis, Minx Patrick, Pitel Frederique, Seiler J. Patrick, Shimmura Tsuyoshi, Tomlinson Chad, Vignal Alain, Webster Robert G., Yoshimura Takashi, Warren Wesley C., Smith Jacqueline

BMC BIOLOGY Vol. 18 ( 1 ) 2020.2

Publisher：BMC Biology

Background: The Japanese quail (Coturnix japonica) is a popular domestic poultry species and an increasingly significant model species in avian developmental, behavioural and disease research. Results: We have produced a high-quality quail genome sequence, spanning 0.93 Gb assigned to 33 chromosomes. In terms of contiguity, assembly statistics, gene content and chromosomal organisation, the quail genome shows high similarity to the chicken genome. We demonstrate the utility of this genome through three diverse applications. First, we identify selection signatures and candidate genes associated with social behaviour in the quail genome, an important agricultural and domestication trait. Second, we investigate the effects and interaction of photoperiod and temperature on the transcriptome of the quail medial basal hypothalamus, revealing key mechanisms of photoperiodism. Finally, we investigate the response of quail to H5N1 influenza infection. In quail lung, many critical immune genes and pathways were downregulated after H5N1 infection, and this may be key to the susceptibility of quail to H5N1. Conclusions: We have produced a high-quality genome of the quail which will facilitate further studies into diverse research questions using the quail as a model avian species.

DOI： 10.1186/s12915-020-0743-4

Interconnection between circadian clocks and thyroid function. Reviewed International coauthorship International journal Open Access

Keisuke Ikegami, Samuel Refetoff, Eve Van Cauter, Takashi Yoshimura

Nature reviews. Endocrinology Vol. 15 ( 10 ) page： 590 - 600 2019.10

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Science and Business Media {LLC}

Circadian rhythmicity is an approximately 24-h cell-autonomous period driven by transcription-translation feedback loops of specific genes, which are referred to as 'circadian clock genes'. In mammals, the central circadian pacemaker, which is located in the hypothalamic suprachiasmatic nucleus, controls peripheral circadian clocks. The circadian system regulates virtually all physiological processes, which are further modulated by changes in the external environment, such as light exposure and the timing of food intake. Chronic circadian disruption caused by shift work, travel across time zones or irregular sleep-wake cycles has long-term consequences for our health and is an important lifestyle factor that contributes to the risk of obesity, type 2 diabetes mellitus and cancer. Although the hypothalamic-pituitary-thyroid axis is under the control of the circadian clock via the suprachiasmatic nucleus pacemaker, daily TSH secretion profiles are disrupted in some patients with hypothyroidism and hyperthyroidism. Disruption of circadian rhythms has been recognized as a perturbation of the endocrine system and of cell cycle progression. Expression profiles of circadian clock genes are abnormal in well-differentiated thyroid cancer but not in the benign nodules or a healthy thyroid. Therefore, the characterization of the thyroid clock machinery might improve the preoperative diagnosis of thyroid cancer.

DOI： 10.1038/s41574-019-0237-z

Action spectrum for photoperiodic control of thyroid-stimulating hormone in Japanese quail (Coturnix japonica) Reviewed Open Access

Nakane Y, Shinomiya A, Ota W, Ikegami K, Shimmura T, Higashi S, Kamei Y, Yoshimura T

PLoS One Vol. 14 ( 9 ) page： e022106 - e0222106 2019.9

The underlying mechanisms of vertebrate seasonal reproduction Invited Reviewed Open Access

Guh Ying-Jey, Tamai Takako Katherine, Yoshimura Takashi

PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES Vol. 95 ( 7 ) page： 343 - 357 2019.7

Publisher：Proceedings of the Japan Academy Series B: Physical and Biological Sciences

Animals make use of changes in photoperiod to adapt their physiology to the forthcoming breeding season. Comparative studies have contributed to our understanding of the mechanisms of seasonal reproduction in vertebrates. Birds are excellent models for studying these phenomena because of their rapid and dramatic responses to changes in photoperiod. Deep brain photoreceptors in birds perceive and transmit light information to the pars tuberalis (PT) in the pituitary gland, where the thyroid-stimulating hormone (TSH) is produced. This PT-TSH locally increases the level of the bioactive thyroid hormone T3 via the induction of type 2 deiodinase production in the mediobasal hypothalamus, and an increased T3 level, in turn, controls seasonal gonadotropin-releasing hormone secretion. In mammals, the eyes are the only photoreceptive structure, and nocturnal melatonin secretion encodes day-length information and regulates the PTTSH signaling cascade. In Salmonidae, the saccus vasculosus plays a pivotal role as a photoperiodic sensor. Together, these studies have uncovered the universality and diversity of fundamental traits in vertebrates.

DOI： 10.2183/pjab.95.025

Casein kinase 1 family regulates PRR5 and TOC1 in the Arabidopsis circadian clock. International coauthorship International journal Open Access

Takahiro N Uehara, Yoshiyuki Mizutani, Keiko Kuwata, Tsuyoshi Hirota, Ayato Sato, Junya Mizoi, Saori Takao, Hiromi Matsuo, Takamasa Suzuki, Shogo Ito, Ami N Saito, Taeko Nishiwaki-Ohkawa, Kazuko Yamaguchi-Shinozaki, Takashi Yoshimura, Steve A Kay, Kenichiro Itami, Toshinori Kinoshita, Junichiro Yamaguchi, Norihito Nakamichi

Proceedings of the National Academy of Sciences of the United States of America Vol. 116 ( 23 ) page： 11528 - 11536 2019.6

Language：English Publishing type：Research paper (scientific journal)

The circadian clock provides organisms with the ability to adapt to daily and seasonal cycles. Eukaryotic clocks mostly rely on lineage-specific transcriptional-translational feedback loops (TTFLs). Posttranslational modifications are also crucial for clock functions in fungi and animals, but the posttranslational modifications that affect the plant clock are less understood. Here, using chemical biology strategies, we show that the Arabidopsis CASEIN KINASE 1 LIKE (CKL) family is involved in posttranslational modification in the plant clock. Chemical screening demonstrated that an animal CDC7/CDK9 inhibitor, PHA767491, lengthens the Arabidopsis circadian period. Affinity proteomics using a chemical probe revealed that PHA767491 binds to and inhibits multiple CKL proteins, rather than CDC7/CDK9 homologs. Simultaneous knockdown of Arabidopsis CKL-encoding genes lengthened the circadian period. CKL4 phosphorylated transcriptional repressors PSEUDO-RESPONSE REGULATOR 5 (PRR5) and TIMING OF CAB EXPRESSION 1 (TOC1) in the TTFL. PHA767491 treatment resulted in accumulation of PRR5 and TOC1, accompanied by decreasing expression of PRR5- and TOC1-target genes. A prr5 toc1 double mutant was hyposensitive to PHA767491-induced period lengthening. Together, our results reveal posttranslational modification of transcriptional repressors in plant clock TTFL by CK1 family proteins, which also modulate nonplant circadian clocks.

DOI： 10.1073/pnas.1903357116

Seasonal regulation of the lncRNA LDAIR modulates self-protective behaviours during the breeding season Open Access

Nakayama Tomoya, Shimmura Tsuyoshi, Shinomiya Ai, Okimura Kousuke, Takehana Yusuke, Furukawa Yuko, Shimo Takayuki, Senga Takumi, Nakatsukasa Mana, Nishimura Toshiya, Tanaka Minoru, Okubo Kataaki, Kamei Yasuhiro, Naruse Kiyoshi, Yoshimura Takashi

NATURE ECOLOGY & EVOLUTION Vol. 3 ( 5 ) page： 845 - 852 2019.5

Cholecystokinin induces crowing in chickens Open Access

Shimmura Tsuyoshi, Tamura Mai, Ohashi Shosei, Sasaki Asuka, TakamichiYamanaka, Nakao Nobuhiro, Ihara Kunio, Okamura Shinsaku, TakashiYoshimura

SCIENTIFIC REPORTS Vol. 9 ( 1 ) 2019.3

Language：Japanese Publisher：Scientific Reports

Animals that communicate using sound are found throughout the animal kingdom. Interestingly, in contrast to human vocal learning, most animals can produce species-specific patterns of vocalization without learning them from their parents. This phenomenon is called innate vocalization. The underlying molecular basis of both vocal learning in humans and innate vocalization in animals remains unknown. The crowing of a rooster is also innately controlled, and the upstream center is thought to be localized in the nucleus intercollicularis (ICo) of the midbrain. Here, we show that the cholecystokinin B receptor (CCKBR) is a regulatory gene involved in inducing crowing in roosters. Crowing is known to be a testosterone (T)-dependent behavior, and it follows that roosters crow but not hens. Similarly, T-administration induces chicks to crow. By using RNA-sequencing to compare gene expression in the ICo between the two comparison groups that either crow or do not crow, we found that CCKBR expression was upregulated in T-containing groups. The expression of CCKBR and its ligand, cholecystokinin (CCK), a neurotransmitter, was observed in the ICo. We also showed that crowing was induced by intracerebroventricular administration of an agonist specific for CCKBR. Our findings therefore suggest that the CCK system induces innate vocalization in roosters.

DOI： 10.1038/s41598-019-40746-9

Involvement of TRPM2 and TRPM8 in temperature-dependent masking behavior International journal Open Access

Ota Wataru, Nakane Yusuke, Kashio Makiko, Suzuki Yoshiro, Nakamura Kazuhiro, Mori Yasuo, Tominaga Makoto, Yoshimura Takashi

SCIENTIFIC REPORTS Vol. 9 ( 1 ) page： 3706 - 3706 2019.3

Language：English Publishing type：Research paper (scientific journal)

Masking is a direct behavioral response to environmental changes and plays an important role in the temporal distribution of activity. However, the mechanisms responsible for masking remain unclear. Here we identify thermosensors and a possible neural circuit regulating temperature-dependent masking behavior in mice. Analysis of mice lacking thermosensitive transient receptor potential (TRP) channels (Trpv1/3/4 and Trpm2/8) reveals that temperature-dependent masking is impaired in Trpm2- and Trpm8-null mice. Several brain regions are activated during temperature-dependent masking, including the preoptic area (POA), known as the thermoregulatory center, the suprachiasmatic nucleus (SCN), which is the primary circadian pacemaker, the paraventricular nucleus of the thalamus (PVT), and the nucleus accumbens (NAc). The POA, SCN, PVT are interconnected, and the PVT sends dense projections to the NAc, a key brain region involved in wheel-running activity. Partial chemical lesion of the PVT attenuates masking, suggesting the involvement of the PVT in temperature-dependent masking behavior.

DOI： 10.1038/s41598-019-40067-x

Photoperiodic Regulation of Reproduction in Vertebrates International journal

Nakane Yusuke, Yoshimura Takashi

ANNUAL REVIEW OF ANIMAL BIOSCIENCES, VOL 7 Vol. 7 page： 173 - 194 2019

Language：English Publishing type：Research paper (scientific journal)

Organisms use changes in photoperiod for seasonal reproduction to maximize the survival of their offspring. Birds have sophisticated seasonal mechanisms and are therefore excellent models for studying these phenomena. Birds perceive light via deep-brain photoreceptors and long day-induced thyroid-stimulating hormone (TSH, thyrotropin) in the pars tuberalis of the pituitary gland (PT), which cause local thyroid hormone activation within the mediobasal hypothalamus. The local bioactive thyroid hormone controls seasonal gonadotropin-releasing hormone secretion and subsequent gonadotropin secretion. In mammals, the eyes are believed to be the only photoreceptor organ, and nocturnal melatonin secretion triggers an endocrine signal that communicates information about the photoperiod to the PT to regulate TSH. In contrast, in Salmonidae fish the input pathway to the neuroendocrine output pathway appears to be localized in the saccus vasculosus. Thus, comparative analysis is an effective way to uncover the universality and diversity of fundamental traits in various organisms.

DOI： 10.1146/annurev-animal-020518-115216

Seasonal changes in color perception

体内時計を標的とした創薬 Invited

吉村崇

実験医学 Vol. 37 page： 398 - 399 2019

脊椎動物の季節感知機構の解明とその応用：動物たちの季節適応戦略の謎に迫る Invited Open Access

中山友哉, 中根右介, 吉村崇

化学と生物 Vol. 57 page： 121 - 128 2019

動物が季節を感じる仕組み Invited

吉村崇

學士會会報 Vol. 936 page： 62 - 66 2019

光と動物の季節性行動 Invited

吉村崇

精神医学 Vol. 61 page： 945 - 953 2019

動物の季節適応機構の解明とその応用：ヒトの季節リズムの解明に向けて Invited Open Access

丸山迪代, 吉村崇

電気泳動 Vol. 63 page： 25 - 29 2019

Impaired Circadian Photoentrainment in Opn5-Null Mice Open Access

Ota Wataru, Nakane Yusuke, Hattar Samer, Yoshimura Takashi

ISCIENCE Vol. 6 page： 299 - + 2018.8

Tsuyoshi Shimmura, Tomoya Nakayama, Ai Shinomiya, Takashi Yoshimura

General and Comparative Endocrinology Vol. 260 page： 171 - 174 2018.5

Language：English Publishing type：Research paper (scientific journal) Publisher：Academic Press Inc.

In temperate zones, organisms experience dynamic fluctuations in environment including changes in color. To cope with such seasonal changes in the environment, organisms adapt their physiology and behavior. Although color perception has been believed to be fixed throughout life, there is increasing evidence for the alteration in opsin gene expression induced by environmental stimuli in a number of animals. Very recently, dynamic seasonal plasticity in color perception has been reported in the seasonally breeding medaka fish. Interestingly, seasonal changes in human color perception have also been reported. Therefore, plasticity of color perception, induced by environmental stimuli, might be a common phenomenon across various species.

DOI： 10.1016/j.ygcen.2017.12.010

Editorial - The Japan Society for Comparative Endocrinology

Yoshimura Takashi, Ukena Kazuyoshi, Takei Yoshio

GENERAL AND COMPARATIVE ENDOCRINOLOGY Vol. 260 page： 162 - 163 2018.5

Identification of circadian clock modulators from existing drugs. International journal Open Access

T Katherine Tamai, Yusuke Nakane, Wataru Ota, Akane Kobayashi, Masateru Ishiguro, Naoya Kadofusa, Keisuke Ikegami, Kazuhiro Yagita, Yasufumi Shigeyoshi, Masaki Sudo, Taeko Nishiwaki-Ohkawa, Ayato Sato, Takashi Yoshimura

EMBO molecular medicine Vol. 10 ( 5 ) 2018.5

Language：English Publishing type：Research paper (scientific journal)

Chronic circadian disruption due to shift work or frequent travel across time zones leads to jet-lag and an increased risk of diabetes, cardiovascular disease, and cancer. The development of new pharmaceuticals to treat circadian disorders, however, is costly and hugely time-consuming. We therefore performed a high-throughput chemical screen of existing drugs for circadian clock modulators in human U2OS cells, with the aim of repurposing known bioactive compounds. Approximately 5% of the drugs screened altered circadian period, including the period-shortening compound dehydroepiandrosterone (DHEA; also known as prasterone). DHEA is one of the most abundant circulating steroid hormones in humans and is available as a dietary supplement in the USA Dietary administration of DHEA to mice shortened free-running circadian period and accelerated re-entrainment to advanced light-dark (LD) cycles, thereby reducing jet-lag. Our drug screen also revealed the involvement of tyrosine kinases, ABL1 and ABL2, and the BCR serine/threonine kinase in regulating circadian period. Thus, drug repurposing is a useful approach to identify new circadian clock modulators and potential therapies for circadian disorders.

DOI： 10.15252/emmm.201708724

Seasonal reproduction: Photoperiodism, birds

Yusuke Nakane, Takashi Yoshimura

Encyclopedia of Reproduction page： 409 - 414 2018.1

Language：English Publishing type：Part of collection (book) Publisher：Elsevier

Seasonal changes in photoperiod are crucial cues for seasonal reproduction in birds inhabiting non-tropical regions. Birds possess photoreceptors in their eyes, pineal organs, and deep brain regions. It is known that birds detect light information of photoperiod, via deep brain photoreceptors. Several studies have revealed that photoinduced thyroid-stimulating hormone, originating from the pars tuberalis of the pituitary gland, prompt the local activation of thyroid hormone in the hypothalamus, which in turn leads to morphological changes in neurons and the secretion of gonadotropin-releasing hormone. In this article, we describe the mechanism for photoperiodism, using the seasonal reproduction of birds as an example.

DOI： 10.1016/B978-0-12-809633-8.20585-2

Seasonal Rhythms: The Role of Thyrotropin and Thyroid Hormones

Nakayama Tomoya, Yoshimura Takashi

THYROID Vol. 28 ( 1 ) page： 4 - 10 2018.1

Seasonal Regulation of Reproduction in Vertebrates: Special Focus on Avian Strategy

Shinomiya Ai, Yoshimura Takashi

REPRODUCTIVE AND DEVELOPMENTAL STRATEGIES: THE CONTINUITY OF LIFE page： 103 - + 2018

季節性と色覚－メダカの色覚は季節によってダイナミックに変化する Invited

新村毅，吉村崇

遺伝 Vol. 72 page： 617 - 622 2018

Dynamic plasticity in phototransduction regulates seasonal changes in color perception Open Access

Tsuyoshi Shimmura, Tomoya Nakayama, Ai Shinomiya, Shoji Fukamachi, Masaki Yasugi, Eiji Watanabe, Takayuki Shimo, Takumi Senga, Toshiya Nishimura, Minoru Tanaka, Yasuhiro Kamei, Kiyoshi Naruse, Takashi Yoshimura

NATURE COMMUNICATIONS Vol. 8 ( 1 ) 2017.12

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

To cope with seasonal changes in the environment, organisms adapt their physiology and behavior. Although color perception varies among seasons, the underlying molecular basis and its physiological significance remain unclear. Here we show that dynamic plasticity in phototransduction regulates seasonal changes in color perception in medaka fish. Medaka are active and exhibit clear phototaxis in conditions simulating summer, but remain at the bottom of the tank and fail to exhibit phototaxis in conditions simulating winter. Mate preference tests using virtual fish created with computer graphics demonstrate that medaka are more attracted to orange-red-colored model fish in summer than in winter. Transcriptome analysis of the eye reveals dynamic seasonal changes in the expression of genes encoding photopigments and their downstream pathways. Behavioral analysis of photopigment-null fish shows significant differences from wild type, suggesting that plasticity in color perception is crucial for the emergence of seasonally regulated behaviors.

DOI： 10.1038/s41467-017-00432-8

The hypothalamic-pituitary-thyroid axis and biological rhythms: The discovery of TSH's unexpected role using animal models. International journal Open Access

Keisuke Ikegami, Takashi Yoshimura

Best practice & research. Clinical endocrinology & metabolism Vol. 31 ( 5 ) page： 475 - 485 2017.10

Language：English Publishing type：Research paper (scientific journal)

Thyroid hormones (TH) are important for development, growth, and metabolism. It is also clear that the synthesis and secretion of TH are regulated by the hypothalamic-pituitary-thyroid (HPT) axis. Animal models have helped advance our understanding of the roles and regulatory mechanisms of TH. The animals' bodies develop through coordinated timing of cell division and differentiation. Studies of frog metamorphosis led to the discovery of TH and their role in development. However, to adapt to rhythmic environmental changes, animals also developed various endocrine rhythms. Studies of rodents clarified the neural and molecular mechanisms underlying the circadian regulation of the HPT axis. Moreover, birds have a sophisticated seasonal adaptation mechanism, and recent studies of quail revealed unexpected roles for thyroid-stimulating hormone (TSH) and TH in the seasonal regulation of reproduction. Interestingly, this mechanism is conserved in mammals. Thus, we review how animal studies have shaped our general understanding of the HPT axis in relation to biological rhythms.

DOI： 10.1016/j.beem.2017.09.002

Molecular mechanism regulating seasonality Reviewed

Keisuke Ikegami, Takashi Yoshimura

Biological Timekeeping: Clocks, Rhythms and Behaviour page： 589 - 605 2017.1

Language：English Publishing type：Part of collection (book) Publisher：Springer (India) Private Ltd.

The mechanisms of vertebrate seasonal time measurement were a mystery for a long time, but recent comparative studies have uncovered the photoperiodic signal transduction cascades in birds, mammals, and fish. These studies reveal the universality and diversity of photoperiodic mechanisms. That is, the molecules involved are conserved, while the tissues responsible for these mechanisms are different in different species (Nakane and Yoshimura, Front Neurosci 8:115, 2014). It is well established that the circadian clock is involved in photoperiodic time measurement. However, the underlying mechanism that defines the photoinducible phase or critical photoperiod (i.e., how organisms measure day length using a circadian clock) is at the heart of photoperiodic time measurement, and this question remains to be answered by future studies.

DOI： 10.1007/978-81-322-3688-7_28

Molecular and neuroendocrine mechanisms of avian seasonal reproduction

T. Katherine Tamai, Takashi Yoshimura

Advances in Experimental Medicine and Biology Vol. 1001 page： 125 - 136 2017

Language：English Publishing type：Part of collection (book) Publisher：Springer New York LLC

Animals living outside tropical zones experience seasonal changes in the environment and accordingly, adapt their physiology and behavior in reproduction, molting, and migration. Subtropical birds are excellent models for the study of seasonal reproduction because of their rapid and dramatic response to changes in photoperiod. For example, testicular weight typically changes by more than a 100-fold. In birds, the eyes are not necessary for seasonal reproduction, and light is instead perceived by deep brain photoreceptors. Functional genomic analysis has revealed that long day (LD)-induced thyrotropin from the pars tuberalis of the pituitary gland causes local thyroid hormone (TH) activation within the mediobasal hypothalamus. This local bioactive TH, triiodothyronine (T3), appears to regulate seasonal gonadotropin-releasing hormone (GnRH) secretion through morphological changes in neuro-glial interactions. GnRH, in turn, stimulates gonadotropin secretion and hence, gonadal development under LD conditions. In marked contrast, low temperatures accelerate short day (SD)-induced testicular regression in winter. Interestingly, low temperatures increase circulating levels of T3 to support adaptive thermogenesis, but this induction of T3 also triggers the apoptosis of germ cells by activating genes involved in metamorphosis. This apparent contradiction in the role of TH has recently been clarified. Central activation of TH during spring results in testicular growth, while peripheral activation of TH during winter regulates adaptive thermogenesis and testicular regression.

DOI： 10.1007/978-981-10-3975-1_8

The Hypothalamo-Pituitary-Thyroid (HPT)-axis: Animal Studies. (in press) Invited Reviewed Open Access

Ikegami K, Yoshimura T

Best Practice & Research Clinical Endocrinology & Metabolism 2017

組織特異的TSH糖鎖修飾 Invited Reviewed

池上啓介, 吉村崇

月刊Mebio Vol. 33 page： 11 - 18 2016.9

Molecular basis for regulating seasonal reproduction in vertebrates Invited Reviewed Open Access

Nishiwaki-Ohkawa T, Yoshimura T

Journal of Endocrinology Vol. 229 ( 3 ) page： R117 - R127 2016.6

Comparative analysis reveals the underlying mechanism of vertebrate seasonal reproduction. Reviewed International journal

Keisuke Ikegami, Takashi Yoshimura

General and comparative endocrinology Vol. 227 page： 64 - 68 2016.2

Language：English Publishing type：Research paper (scientific journal)

Animals utilize photoperiodic changes as a calendar to regulate seasonal reproduction. Birds have highly sophisticated photoperiodic mechanisms and functional genomics analysis in quail uncovered the signal transduction pathway regulating avian seasonal reproduction. Birds detect light with deep brain photoreceptors. Long day (LD) stimulus induces secretion of thyroid-stimulating hormone (TSH) from the pars tuberalis (PT) of the pituitary gland. PT-derived TSH locally activates thyroid hormone (TH) in the hypothalamus, which induces gonadotropin-releasing hormone (GnRH) and hence gonadotropin secretion. However, during winter, low temperatures increase serum TH for adaptive thermogenesis, which accelerates germ cell apoptosis by activating the genes involved in metamorphosis. Therefore, TH has a dual role in the regulation of seasonal reproduction. Studies using TSH receptor knockout mice confirmed the involvement of PT-derived TSH in mammalian seasonal reproduction. In addition, studies in mice revealed that the tissue-specific glycosylation of TSH diversifies its function in the circulation to avoid crosstalk. In contrast to birds and mammals, one of the molecular machineries necessary for the seasonal reproduction of fish are localized in the saccus vasculosus from the photoreceptor to the neuroendocrine output. Thus, comparative analysis is a powerful tool to uncover the universality and diversity of fundamental properties in various organisms.

DOI： 10.1016/j.ygcen.2015.05.009

Different photoperiodic responses in four lines of Japanese quail. Reviewed Open Access

Yusuke Atsumi, Eriko Yorinaga, Wataru Ota, Takashi Yoshimura

The Journal of Poultry Science Vol. 53 ( 1 ) page： 63 - 66 2016.1

Language：English Publishing type：Research paper (scientific journal) Publisher：Japan Poultry Science Association

Organisms measure day length to better adapt to seasonal changes in the environment; this phenomenon is called photoperiodism. The Japanese quail has a highly sophisticated photoperiodic mechanism and is an excellent model for the study of photoperiodism. Various lines of quail have been established during the domestication process. In the present study, we examined the effect of long day (LD) followed by short day (SD) on testicular weight in four lines of quail (L, AMRP, NIES-Br, and WE). When the quail were raised under SD conditions, testicular development was suppressed in all examined lines. The speed of the LD-induced testicular development of NIES-Br line was faster than that of AMRP line, while the speed of the SD-induced testicular regression of L line was significantly faster than that of WE line. These quail lines provide excellent model to uncover the underlying mechanism of seasonal testicular regression.

DOI： 10.2141/jpsa.0150097

Other Link： https://jlc.jst.go.jp/DN/JLC/20019782070?from=CiNii

春告げホルモンTSHが甲状腺を刺激しない仕組み Invited

吉村崇

内分泌・糖尿病・代謝内科 Vol. 42 page： 58 - 62 2016

脊椎動物の光周性制御機構 Invited

中根右介, 吉村崇

生体の科学 Vol. 67 page： 1 - 4 2016

組織特異的TSH糖鎖修飾 Invited

池上啓介, 吉村崇

月間Mebio Vol. 33 page： 11 - 18 2016

なぜ動物は種特有の鳴き方ができるのか？ニワトリの「コケコッコー」を用いた先天的発声の研究 Invited

新村毅, 吉村崇

実験医学 Vol. 34 page： 618 - 621 2016

Lactic acid is a sperm motility inactivation factor in the sperm storage tubules Open Access

Mei Matsuzaki, Shusei Mizushima, Gen Hiyama, Noritaka Hirohashi, Kogiku Shiba, Kazuo Inaba, Tomohiro Suzuki, Hideo Dohra, Toshiyuki Ohnishi, Yoshikatsu Sato, Tetsuya Kohsaka, Yoshinobu Ichikawa, Yusuke Atsumi, Takashi Yoshimura, Tomohiro Sasanami

SCIENTIFIC REPORTS Vol. 5 2015.12

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Although successful fertilization depends on timely encounters between sperm and egg, the decoupling of mating and fertilization often confers reproductive advantages to internally fertilizing animals. In several vertebrate groups, postcopulatory sperm viability is prolonged by storage in specialized organs within the female reproductive tract. In birds, ejaculated sperm can be stored in a quiescent state within oviductal sperm storage tubules (SSTs), thereby retaining fertilizability for up to 15 weeks at body temperature (41 degrees C); however, the mechanism by which motile sperm become quiescent within SSTs is unknown. Here, we show that low oxygen and high lactic acid concentrations are established in quail SSTs. Flagellar quiescence was induced by lactic acid in the concentration range found in SSTs through flagellar dynein ATPase inactivation following cytoplasmic acidification (<pH 6.0). The long-term preservation of sperm morphology under hypoxic and high temperature conditions indicates that a combination of these factors enables sperm cells to survive during the ovulation cycles. Our findings suggested a novel physiological role for lactic acid in promoting sperm quiescence in SSTs and opened up a new opportunity for technological improvement in prolonging sperm longevity at ambient or body temperature.

DOI： 10.1038/srep17643

Ontogeny of the Saccus Vasculosus, a Seasonal Sensor in Fish. Reviewed Open Access

Maeda R, Shimo T, Nakane Y, Nakao N, Yoshimura T

Endocrinology Vol. 156 ( 11 ) page： 4238 - 4243 2015.11

Disrupted seasonal biology impacts health, food security, and ecosystems Reviewed International coauthorship Open Access

Stevenson TJ, Visser ME, Arnold W, Barrett P, Biello S, Dawson A, Denlinger DL, Dominoni D, Ebling FJ, Elton S, Evans N, Ferguson HM, Foster RG, Hau M, Haydon DT, Hazlerigg DG, Heideman P, Hopcraft JGC, Jonsson NN, Kronfeld-Schor N, Kumar V, Lincoln GA, MacLeod R, Martin SAM, Martinez-Bakker, M, Nelson RJ, Reed T, Robinson JE, Rock D, Schwartz WJ, Steffan-Dewenter I, Tauber E, Thackeray SJ, Umstatter C, Yoshimura T, Helm B

Proceedings of the Royal Society B Vol. 282 ( 1817 ) page： 1817 2015.10

Animals' clever adaptation strategy for seasonal changes in environment

Ikegami Keisuke, Yoshimura Takashi

JAPANESE JOURNAL OF NEUROPSYCHOPHARMACOLOGY Vol. 35 ( 4 ) page： 103 - 106 2015.8

The highest-ranking rooster has priority to announce the break of dawn Reviewed Open Access

Tsuyoshi Shimmura, Shosei Ohashi, Takashi Yoshimura

SCIENTIFIC REPORTS Vol. 5 2015.7

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

The "cock-a-doodle-doo" crowing of roosters, which symbolizes the break of dawn in many cultures, is controlled by the circadian clock. When one rooster announces the break of dawn, others in the vicinity immediately follow. Chickens are highly social animals, and they develop a linear and fixed hierarchy in small groups. We found that when chickens were housed in small groups, the top-ranking rooster determined the timing of predawn crowing. Specifically, the top-ranking rooster always started to crow first, followed by its subordinates, in descending order of social rank. When the top-ranking rooster was physically removed from a group, the second-ranking rooster initiated crowing. The presence of a dominant rooster significantly reduced the number of predawn crows in subordinates. However, the number of crows induced by external stimuli was independent of social rank, confirming that subordinates have the ability to crow. Although the timing of subordinates' predawn crowing was strongly dependent on that of the top-ranking rooster, free-running periods of body temperature rhythms differed among individuals, and crowing rhythm did not entrain to a crowing sound stimulus. These results indicate that in a group situation, the top-ranking rooster has priority to announce the break of dawn, and that subordinate roosters are patient enough to wait for the top-ranking rooster's first crow every morning and thus compromise their circadian clock for social reasons.

DOI： 10.1038/srep11683

C-H Activation Generates Period-Shortening Molecules That Target Cryptochrome in the Mammalian Circadian Clock

Oshima Tsuyoshi, Yamanaka Iori, Kumar Anupriya, Yamaguchi Junichiro, Nishiwaki-Ohkawa Taeko, Muto Kei, Kawamura Rika, Hirota Tsuyoshi, Yagita Kazuhiro, Irle Stephan, Kay Steve A., Yoshimura Takashi, Itami Kenichiro

ANGEWANDTE CHEMIE-INTERNATIONAL EDITION Vol. 54 ( 24 ) page： 7193 - 7197 2015.6

Low Temperature-Induced Circulating Triiodothyronine Accelerates Seasonal Testicular Regression Open Access

Ikegami Keisuke, Atsumi Yusuke, Yorinaga Eriko, Ono Hiroko, Murayama Itaru, Nakane Yusuke, Ota Wataru, Arai Natsumi, Tega Akinori, Iigo Masayuki, Darras Veerle M., Tsutsui Kazuyoshi, Hayashi Yoshitaka, Yoshida Shosei, Yoshimura Takashi

ENDOCRINOLOGY Vol. 156 ( 2 ) page： 647 - 659 2015.2

A unique mechanism of successful fertilization in a domestic bird Open Access

Tomohiro Sasanami, Shunsuke Izumi, Naoki Sakurai, Toshifumi Hirata, Shusei Mizushima, Mei Matsuzaki, Gen Hiyama, Eriko Yorinaga, Takashi Yoshimura, Kazuyoshi Ukena, Kazuyoshi Tsutsui

SCIENTIFIC REPORTS Vol. 5 2015.1

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Fertilization is an indispensable step for formation of a zygote in sexual reproduction, leading to species survival. When mating occurs, sperm is transported to the female reproductive tracts via the seminal plasma (SP). SP is derived from male accessory sex glands and it plays pivotal roles for fertilization in animals. However, molecular mechanisms of SP or a fluid derived from male accessory sex glands for successful fertilization remain unclear. Here, we report that in male quail the cloacal gland (CG) produces prostaglandin F-2 alpha (PGF(2 alpha)) that contributes to successful fertilization. PGF(2 alpha), as well as the secretion of CG (CGS), induced vaginal contractions and caused the opening of the entrance of the sperm storage tubules, the structures responsible for the long-term sperm storage and fertilization. The removal of CGS from the male before mating reduced the fertility, but the supplementation of CGS or PGF(2 alpha) rescued the subfertility. We further showed that male CG contains glucose that is utilized as energy source for the intrinsic sperm mobility after transportation to female vagina. This mechanism, in concert with the excitatory effects of PGF(2 alpha) enables successful fertilization in the domestic bird.

DOI： 10.1038/srep07700

季節感知機構の解析から見えてきた動物の巧みな戦略 Invited Reviewed

池上啓介, 吉村崇

日本神経精神薬理学雑誌 Vol. 35 ( 4 ) page： 103 - 106 2015

ホルモンの糖鎖修飾による巧みな生理機能の分担戦略 Invited Reviewed

池上啓介, 吉村崇

日本比較内分泌学会 Vol. 41 ( 156 ) page： 127 - 128 2015

Circannual Cycles and Photoperiodism

Cassone Vincent M., Yoshimura Takashi

STURKIE'S AVIAN PHYSIOLOGY, 6TH EDITION page： 829 - 845 2015

季節感知機構の解析から見えてきた動物の巧みな戦略 Invited

池上啓介, 吉村崇

日本神経精神薬理学雑誌 Vol. 35 page： 103 - 106 2015

触媒で体内時計のリズムを変える－異分野融合がもたらした新分子の発見 Invited

伊丹健一郎, 吉村崇

月刊化学 Vol. 70 page： 32 - 36 2015

ホルモンの糖鎖修飾による巧みな生理機能の分担戦略 Invited

池上啓介, 吉村崇

比較内分泌学 Vol. 41 page： 129 - 130 2015

Takashi Yoshimura Open Access

Yoshimura Takashi

CURRENT BIOLOGY Vol. 24 ( 23 ) page： R1108 - R1109 2014.12

Tissue-specific post-translational modification allows functional targeting of thyrotropin Reviewed Open Access

Ikegami K, Liao XH, Hoshino Y, Ono H, Ota W, Ito Y, Nishiwaki-Ohkawa T, Sato C, Kitajima K, Iigo M, Shigeyoshi Y, Yamada M, Murata Y, Refetoff S, Yoshimura T

Cell Reports Vol. 9 page： 801-809 2014.11

Thyrotoropin receptor knockout changes monoaminergic neuronal system and produces methylphenidate-sensitive emotional and cognitive dysfunction. Reviewed International journal

Akihiro Mouri, Yuta Hoshino, Shiho Narusawa, Keisuke Ikegami, Hiroyuki Mizoguchi, Yoshiharu Murata, Takashi Yoshimura, Toshitaka Nabeshima

Psychoneuroendocrinology Vol. 48 page： 147 - 161 2014.10

Language：English Publishing type：Research paper (scientific journal)

Attention deficit/hyperactivity disorder (ADHD) has been reported in association with resistance to thyroid hormone, a disease caused by a mutation in the thyroid hormone receptor β (TRβ) gene. TRβ is a key protein mediating down-regulation of thyrotropin (TSH) expression by 3,3',5-tri-iodothyronine (T3), an active form of thyroid hormone. Dysregulation of TSH and its receptor (TSHR) is implicated in the pathophysiology of ADHD but the role of TSHR remains elusive. Here, we clarified a novel role for TSHR in emotional and cognitive functions related to monoaminergic nervous systems. TSHR knockout mice showed phenotypes of ADHD such as hyperactivity, impulsiveness, a decrease in sociality and increase in aggression, and an impairment of short-term memory and object recognition memory. Administration of methylphenidate (1, 5 and 10mg/kg) reversed impulsiveness, aggression and object recognition memory impairment. In the knockout mice, monoaminergic changes including decrease in the ratio of 3-methoxy-4-hydroxyphenylglycol/noradrenaline and increase in the ratio of homovanillic acid/dopamine were observed in some brain regions, accompanied by increase in the expression of noradrenaline transporter in the frontal cortex. When TSH was completely suppressed by the supraphysiological administration of T3 to the adult mice, some behavioral and neurological changes in TSHR KO mice were also observed, suggesting that these changes were not due to developmental hypothyroidism induced by the inactivation of TSHR but to the loss of the TSH-TSHR pathway itself. Taken together, the present findings suggest a novel role for TSHR in behavioral and neurological phenotypes of ADHD.

DOI： 10.1016/j.psyneuen.2014.05.021

Intrinsic photosensitivity of a deep brain photoreceptor Open Access

Yusuke Nakane, Tsuyoshi Shimmura, Hideki Abe, Takashi Yoshimura

CURRENT BIOLOGY Vol. 24 ( 13 ) page： R596 - R597 2014.7

Universality and diversity in the signal transduction pathway that regulates seasonal reproduction in vertebrates Invited Reviewed Open Access

Yusuke Nakane, Takashi Yoshimura

FRONTIERS IN NEUROSCIENCE Vol. 8 ( 8 MAY ) page： 115 2014.5

Language：English Publisher：FRONTIERS RESEARCH FOUNDATION

Most vertebrates living outside the tropical zone show robust physiological responses in response to seasonal changes in photoperiod, such as seasonal reproduction, molt, and migration. The highly sophisticated photoperiodic mechanism in Japanese quail has been used to uncover the mechanism of seasonal reproduction. Molecular analysis of quail mediobasal hypothalamus (MBH) revealed that local thyroid hormone activation within the MBH plays a critical role in the photoperiodic response of gonads. This activation is accomplished by two gene switches: thyroid hormone-activating (DIO2) and thyroid hormone-inactivating enzymes (DIO3). Functional genomics studies have shown that long-day induced thyroid-stimulating hormone (TSH) in the pars tuberalis (PT) of the pituitary gland regulates DIO2/3 switching. In birds, light information received directly by deep brain photoreceptors regulates PT TSH. Recent studies demonstrated that Opsin 5-positive cerebrospinal fluid (CSF)-contacting neurons are deep brain photoreceptors that regulate avian seasonal reproduction. Although the involvement of TSH and DIO2/3 in seasonal reproduction has been confirmed in various mammals, the light input pathway that regulates PT TSH in mammals differs from that of birds. In mammals, the eye is the only photoreceptor organ and light information received by the eye is transmitted to the pineal gland through the circadian pacemaker, the suprachiasmatic nucleus. Nocturnal melatonin secretion from the pineal gland indicates the length of night and regulates the PT TSH. In fish, the regulatory machinery for seasonal reproduction, from light input to neuroendocrine output, has been recently demonstrated in the coronet cells of the saccus vasculosus (SV). The SV is unique to fish and coronet cells are CSF-contacting neurons. Here, we discuss the universality and diversity of signal transduction pathways that regulate vertebrate seasonal reproduction.

DOI： 10.3389/fnins.2014.00115

Sperm activation by heat shock protein 70 supports the migration of sperm released from sperm storage tubules in Japanese quail (Coturnix japonica). Reviewed International journal Open Access

Gen Hiyama, Mei Matsuzaki, Shusei Mizushima, Hideo Dohra, Keisuke Ikegami, Takashi Yoshimura, Kogiku Shiba, Kazuo Inaba, Tomohiro Sasanami

Reproduction (Cambridge, England) Vol. 147 ( 2 ) page： 167 - 178 2014.2

Language：English Publishing type：Research paper (scientific journal)

Systems for maintaining the viability of ejaculated sperm in the female reproductive tract are widespread among vertebrates and invertebrates. In birds, this sperm storage function is performed by specialized simple tubular invaginations called sperm storage tubules (SSTs) in the uterovaginal junction (UVJ) of the oviduct. Although the incidence and physiological reasons for sperm storage in birds have been reported extensively, the mechanisms of sperm uptake by the SSTs, sperm maintenance within the SSTs, and control of sperm release from the SSTs are poorly understood. In this study, we demonstrated that the highly conserved heat shock protein 70 (HSP70) stimulates sperm motility in vitro and also that HSP70 expressed in the UVJ may facilitate the migration of sperm released from the SSTs. Quantitative RT-PCR analysis demonstrated that the expression of HSP70 mRNA in the UVJ increases before ovulation/oviposition. Gene-specific in situ hybridization and immunohistochemical analysis with a specific antibody to HSP70 demonstrated that HSP70 is localized in the surface epithelium of the UVJ. Furthermore, injection of anti-HSP70 antibody into the vagina significantly inhibited fertilization in vivo. In addition, we found that recombinant HSP70 activates flagellar movement in the sperm and that the binding of recombinant HSP70 to the sperm surface is mediated through an interaction with voltage-dependent anion channel protein 2 (VDAC2). Our results suggest that HSP70 binds to the sperm surface by interacting with VDAC2 and activating sperm motility. This binding appears to play an important role in sperm migration within the oviduct.

DOI： 10.1530/REP-13-0439

Helix-loop-helix protein Id2 stabilizes mammalian circadian oscillation under constant light conditions. Reviewed

Seasonal sensor in fish

Comparative Endocrinology Vol. 40 ( 152 ) page： 65 - 67 2014

Regulation of seasonal reproduction by hypothalamic activation of thyroid hormone. Reviewed International journal Open Access

Shinomiya A, Shimmura T, Nishiwaki-Ohkawa, T, Yoshimura T

Frontiers in Endocrinology Vol. 5 ( FEB ) page： 12 - 12 2014

Language：English Publishing type：Research paper (scientific journal)

Organisms living outside the tropics measure the changes in the length of the day to adapt to seasonal changes in the environment. Animals that breed during spring and summer are called long-day breeders, while those that breed during fall are called short-day breeders. Although the influence of thyroid hormone in the regulation of seasonal reproduction has been known for several decades, its precise mechanism remained unknown. Recent studies revealed that the activation of thyroid hormone within the mediobasal hypothalamus plays a key role in this phenomenon. This localized activation of the thyroid hormone is controlled by thyrotropin (thyroid-stimulating hormone) secreted from the pars tuberalis of the pituitary gland. Although seasonal reproduction is a rate-limiting factor in animal production, genes involved in photoperiodic signal transduction pathway could emerge as potential targets to facilitate domestication.

DOI： 10.3389/fendo.2014.00012

季節リズムの制御メカニズム Invited

大川妙子, 吉村崇

睡眠医療 Vol. 8 page： 203 - 209 2014

Akihito A Adachi, Atsuko Fujioka, Mamoru Nagano, Koh-hei Masumoto, Toru Takumi, Takashi Yoshimura, Shizufumi Ebihara, Kentaro Mori, Yoshifumi Yokota, Yasufumi Shigeyoshi

Zoological science Vol. 30 ( 12 ) page： 1011 - 1018 2013.12

Language：English Publishing type：Research paper (scientific journal)

The mammalian circadian oscillator is composed of interacting positive and negative transcription events. The clock proteins PER1 and PER2 play essential roles in a negative limb of the feedback loop that generates the circadian rhythm in mammals. In addition, the proteins CLOCK and BMAL1 (also known as ARNTL) form a heterodimer that drives the Per genes via the E-box consensus sequences within their promoter regions. In the present study, we demonstrate that Id2 is involved in stabilization of the amplitudes of the circadian oscillations by suppressing transcriptional activation of clock genes Clock and Bmal1. Id2 shows dynamic oscillation in the SCN, with a peak in the late subjective night. Under constant dark conditions (DD), Id2(-/-) mice showed no apparent difference in locomotor activity, however, under constant light conditions (LL), Id2(-/-) mice exhibit aberrant locomotor activity, with lower circadian oscillation amplitudes, although the free running periods in Id2(-/-) mice show no differences from those in either wild type or heterozygous mice. Id2(-/-) animals also exhibit upregulation of Per1 in constant light, during both the subjective night and day. In wild type mice, Id2 is upregulated by constant light exposure during the subjective night. We propose that Id2 expression in the SCN contributes to maintenance of dynamic circadian oscillations.

DOI： 10.2108/zsj.30.1011

Thyroid hormone and seasonal regulation of reproduction Invited Reviewed

Yoshimura T

Frontiers in Neuroendocrinology Vol. 34 ( 3 ) page： 157 - 166 2013.8

Seasonal time measurement during reproduction. Reviewed Open Access

Keisuke Ikegami, Takashi Yoshimura

The Journal of reproduction and development Vol. 59 ( 4 ) page： 327 - 333 2013.8

Language：English Publishing type：Research paper (scientific journal)

Most species living outside the tropical zone undergo physiological adaptations to seasonal environmental changes and changing day length (photoperiod); this phenomenon is called photoperiodism. It is well known that the circadian clock is involved in the regulation of photoperiodism such as seasonal reproduction, but the mechanism underlying circadian clock regulation of photoperiodism remains unclear. Recent molecular analysis have revealed that, in mammals and birds, the pars tuberalis (PT) of the pituitary gland acts as the relay point from light receptors, which receive information about the photoperiod, to the endocrine responses. Long-day (LD)-induced thyroid-stimulating hormone (TSH) in the PT acts as a master regulator of seasonal reproduction in the ependymal cells (ECs) within the mediobasal hypothalamus (MBH) and activates thyroid hormone (TH) by inducing the expression of type 2 deiodinase in both LD and short-day (SD) breeding animals. Furthermore, the circadian clock has been found to be localized in the PT and ECs as well as in the circadian pacemaker(s). This review purposes to summarize the current knowledge concerning the involvement of the neuroendocrine system and circadian clock in seasonal reproduction.

DOI： 10.1262/jrd.2013-035

The saccus vasculosus of fish is a sensor of seasonal changes in day length Open Access

Nakane Yusuke, Ikegami Keisuke, Iigo Masayuki, Ono Hiroko, Takeda Korenori, Takahashi Daisuke, Uesaka Maiko, Kimijima Meita, Hashimoto Ramu, Arai Natsumi, Suga Takuya, Kosuge Katsuya, Abe Tomotaka, Maeda Ryosuke, Senga Takumi, Amiya Noriko, Azuma Teruo, Amano Masafumi, Abe Hideki, Yamamoto Naoyuki, Yoshimura Takashi

NATURE COMMUNICATIONS Vol. 4 2013.7

Next-generation sequencing reveals genomic features in the Japanese quail Reviewed Open Access

Ryouka Kawahara-Miki, Satoshi Sano, Mitsuo Nunome, Tsuyoshi Shimmura, Takehito Kuwayama, Shinji Takahashi, Takaharu Kawashima, Yoichi Matsuda, Takashi Yoshimura, Tomohiro Kono

GENOMICS Vol. 101 ( 6 ) page： 345 - 353 2013.6

Language：English Publishing type：Research paper (scientific journal) Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE

The Japanese quail has several advantages as a laboratory animal for biological and biomedical investigations. In this study, the draft genome of the Japanese quail was sequenced and assembled using next-generation sequencing technology. To improve the quality of the assembly, the sequence reads from the Japanese quail were aligned against the reference genome of the chicken. The final draft assembly consisted of 1.75 Gbp with an N50 contig length of 11,409 bp. On the basis of the draft genome sequence obtained, we developed 100 microsatellite markers and used these markers to evaluate the genetic variability and diversity of 11 lines of Japanese quail. Furthermore, we identified Japanese quail orthologs of spermatogenesis markers and analyzed their expression using in situ hybridization. The Japanese quail genome sequence obtained in the present study could enhance the value of this species as a model animal. (C) 2013 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.ygeno.2013.03.006

Understanding mechanism of seasonal reproduction and deep brain photoreceptor

Other Link： http://orcid.org/0000-0003-2072-8851

Circadian clock determines the timing of rooster crowing Reviewed Open Access

Tsuyoshi Shimmura, Takashi Yoshimura

CURRENT BIOLOGY Vol. 23 ( 6 ) page： R231 - R233 2013.3

Circadian clock gene Per2 is not necessary for the photoperiodic response in mice. Reviewed International journal Open Access

Keisuke Ikegami, Masayuki Iigo, Takashi Yoshimura

PloS one Vol. 8 ( 3 ) page： e58482 2013.3

Language：English Publishing type：Research paper (scientific journal)

In mammals, light information received by the eyes is transmitted to the pineal gland via the circadian pacemaker, i.e., the suprachiasmatic nucleus (SCN). Melatonin secreted by the pineal gland at night decodes night length and regulates seasonal physiology and behavior. Melatonin regulates the expression of the β-subunit of thyroid-stimulating hormone (TSH; Tshb) in the pars tuberalis (PT) of the pituitary gland. Long day-induced PT TSH acts on ependymal cells in the mediobasal hypothalamus to induce the expression of type 2 deiodinase (Dio2) and reduce type 3 deiodinase (Dio3) that are thyroid hormone-activating and hormone-inactivating enzymes, respectively. The long day-activated thyroid hormone T3 regulates seasonal gonadotropin-releasing hormone secretion. It is well established that the circadian clock is involved in the regulation of photoperiodism. However, the involvement of the circadian clock gene in photoperiodism regulation remains unclear. Although mice are generally considered non-seasonal animals, it was recently demonstrated that mice are a good model for the study of photoperiodism. In the present study, therefore, we examined the effect of changing day length in Per2 deletion mutant mice that show shorter wheel-running rhythms under constant darkness followed by arhythmicity. Although the amplitude of clock gene (Per1, Cry1) expression was greatly attenuated in the SCN, the expression profile of arylalkylamine N-acetyltransferase, a rate-limiting melatonin synthesis enzyme, was unaffected in the pineal gland, and robust photoperiodic responses of the Tshb, Dio2, and Dio3 genes were observed. These results suggested that the Per2 clock gene is not necessary for the photoperiodic response in mice.

DOI： 10.1371/journal.pone.0058482

新規光受容器「オプシン5」欠損マウスの行動解析

太田航, 中根右介, 池上啓介, 吉村崇

日本畜産学会大会講演要旨集 Vol. 116回 page： 97 - 97 2013.3

脊椎動物の光周性の制御機構 Invited

頼永恵理子, 吉村崇

生物科学 Vol. 64 page： 205 - 211 2013

脊椎動物が季節を感知する仕組みの解明 Invited Reviewed

前田遼介, 吉村崇

トレーサー Vol. 54 page： 3 - 8 2013

哺乳類における新規光受容器Opsin 5の発現解析

太田航, 中根右介, 池上啓介, 吉村崇

日本畜産学会大会講演要旨集 Vol. 115回 page： 216 - 216 2012.3

Circadian clocks and the measurement of daylength in seasonal reproduction

Ikegami Keisuke, Yoshimura Takashi

MOLECULAR AND CELLULAR ENDOCRINOLOGY Vol. 349 ( 1 ) page： 76 - 81 2012.2

Nakane Y., Yoshimura T.

Seikagaku Vol. 83 ( 2 ) page： 114 - 117 2011.12

Photoperiodism in vertebrates.

Wataru Ota, Takashi Yoshimura

Journal of the Society of Biomechanisms Vol. 35 ( 4 ) page： 251 - 257 2011.11

Progesterone Is a Sperm-Releasing Factor from the Sperm-Storage Tubules in Birds Open Access

Ito Tomomi, Yoshizaki Norio, Tokumoto Toshinobu, Ono Hiroko, Yoshimura Takashi, Tsukada Akira, Kansaku Norio, Sasanami Tomohiro

ENDOCRINOLOGY Vol. 152 ( 10 ) page： 3952 - 3962 2011.10

ウズラの季節性精巣退縮機構の解明

渥美優介, 池上啓介, 小野ひろ子, 村山至, 中根右介, 太田航, 新井菜津美, 手賀明倫, 飯郷雅之, 吉田松生, 吉村崇

The Journal of Reproduction and Development Vol. 57 ( Suppl. ) page： j103 - j103 2011.8

Opsin 5 as a deep brain photoreceptor regulating photoperiodism

Yusuke Nakane, Keisuke Ikegami, Hiroko Ono, Naoyuki Yamamoto, Shosei Yoshida, Yasuhiro Kamei, Sho-ichi Higashi, Kanjun Hirunagi, Shizufumi Ebihara, Yoshihiro Kubo, Takashi Yoshimura

NEUROSCIENCE RESEARCH Vol. 71 page： E171 - E171 2011

Oocytic expression of zona pellucida protein ZP4 in Japanese quail (Coturnix japonica)

Serizawa Mami, Kinoshita Mihoko, Rodler Daniela, Tsukada Akira, Ono Hiroko, Yoshimura Takashi, Kansaku Norio, Sasanami Tomohiro

ANIMAL SCIENCE JOURNAL Vol. 82 ( 2 ) page： 227 - 235 2011

Publisher：Animal Science Journal

The avian perivitelline layer, an extracellular matrix homologous to the zona pellucida (ZP) of mammalian oocytes, is composed mainly by zona pellucida gene family glycoproteins. Our previous studies in Japanese quail have demonstrated that the matrix's components, ZP3 and ZPD, are synthesized in ovarian granulosa cells. Another component, ZP1, is synthesized in the liver. Recently, we demonstrated that another minor constituent, ZP2 is produced in the oocytes of the immature follicles. In the present study, we report the isolation of complementary DNA encoding quail ZP4 and its expression and origin in the female birds. By ribonuclease protection assay and in situ hybridization, we demonstrated that ZP4 transcripts were transcribed in the oocytes of small white follicles. The expression level of ZP4 decreased dramatically during follicular development, and the highest expression was observed in the small white follicles. Western blot analysis using the specific antibody against ZP4 indicated that the immunoreactive 58.2kDa protein was present in the lysates of the small white follicles. These results demonstrate for the first time that the avian ZP4 is expressed in the oocyte, and that the expression pattern of the gene is similar to that of ZP2. © 2011 The Authors. Journal compilation © 2011 Japanese Society of Animal Science.

DOI： 10.1111/j.1740-0929.2010.00830.x

Deep brain photoreceptors and a seasonal signal transduction cascade in birds

季節繁殖の制御機構と脳深部光受容器の解明 Invited

中根右介, 吉村崇

生化学 Vol. 83 page： 114 - 117 2011

脊椎動物の光周性 Invited Open Access

太田航, 吉村崇

バイオメカニズム学会誌 Vol. 35 page： 251 - 257 2011

Yusuke Nakane, Takashi Yoshimura

CELL AND TISSUE RESEARCH Vol. 342 ( 3 ) page： 341 - 344 2010.12

A mammalian neural tissue opsin (Opsin 5) is a deep brain photoreceptor in birds Open Access

Nakane Yusuke, Ikegami Keisuke, Ono Hiroko, Yamamoto Naoyuki, Yoshida Shosei, Hirunagi Kanjun, Ebihara Shizufumi, Kubo Yoshihiro, Yoshimura Takashi

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vol. 107 ( 34 ) page： 15264 - 15268 2010.8

Usp46, encoding a ubiquitin specific peptidase, is a quantitative trait gene underlying "behavioral despair" in mice Reviewed

Shizufumi Ebihara, Shigeru Tomida, Takayoshi Mamiya, Hirotake Sakamaki, Masami Miura, Toshihiko Aosaki, Masao Masuda, Minae Niwa, Tsutomu Kameyama, Junya Kobayashi, Yuka Iwaki, Saki Imai, Akira Ishikawa, Kuniya Abe, Takashi Yoshimura, Toshitaka Nabeshima

SLEEP AND BIOLOGICAL RHYTHMS Vol. 8 ( 2 ) page： 114 - 119 2010.4

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

CS mice exhibit several distinct phenotypes of circadian behavioral rhythms and sleep properties. Because many mental illnesses are associated with abnormalities in the circadian rhythms and sleep pattern, we characterized the behavioral phenotypes in CS mice with a battery of behavioral tests. Among these phenotypes, we found that CS mice exhibit an extremely low immobility time in both the tail suspension test (TST) and forced swimming test (FST). To uncover the genetic basis for lower immobility time, we first performed quantitative trait locus (QTL) mapping using CS and C57BL/6J mice, which revealed significant QTLs on chromosomes (Chrs) 4 (FST) and 5 (TST and FST). To identify the quantitative trait gene on Chr 5, we narrowed the QTL interval to 0.5 Mb using several congenic and subcongenic strains. Ubiquitin-specific peptidase 46 (Usp46) with a lysine codon deletion was located in this region. This deletion affected nest-building, muscimol-induced righting reflex, and anti-immobility effects of imipramine. The muscimol-induced current in the hippocampal CA1 pyramidal neurons and hippocampal expression of the 67-kDa isoform of glutamic acid decarboxylase significantly decreased in Usp46 mutant mice. All these phenotypes were rescued in transgenic mice with bacterial artificial chromosomes containing wild-type Usp46. Thus, Usp46 affects the immobility in the TST and FST, and it is implicated in the regulation of GABA action.

DOI： 10.1111/j.1479-8425.2010.00435.x

Influence of the estrous cycle on clock gene expression in reproductive tissues: Effects of fluctuating ovarian steroid hormone levels Reviewed Open Access

Takahiro J. Nakamura, Michael T. Sellix, Takashi Kudo, Nobuhiro Nakao, Takashi Yoshimura, Shizufumi Ebihara, Christopher S. Colwell, Gene D. Block

STEROIDS Vol. 75 ( 3 ) page： 203 - 212 2010.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Circadian rhythms in physiology and behavior are known to be influenced by the estrous cycle in female rodents. The clock genes responsible for the generation of circadian oscillations are widely expressed both within the central nervous system and peripheral tissues, including those that comprise the reproductive system. To address whether the estrous cycle affects rhythms of clock gene expression in peripheral tissues, we first examined rhythms of clock gene expression (Per1, Per2, Bmal1) in reproductive (uterus, ovary) and non-reproductive (liver) tissues of cycling rats using quantitative real-time PCR (in vivo) and luminescent recording methods to measure circadian rhythms of PER2 expression in tissue explant cultures from cycling PER2:: LUCIFERASE (PER2::LUC) knockin mice (ex vivo). We found significant estrous variations of clock gene expression in all three tissues in vivo, and in the uterus ex Vivo. We also found that exogenous application of estrogen and progesterone altered rhythms of PER2::LUC expression in the uterus. In addition, we measured the effects of ovarian steroids on clock gene expression in a human breast cancer cell line (MCF-7 cells) as a model for endocrine cells that contain both the steroid hormone receptors and clock genes, We found that progesterone, but not estrogen, acutely up-regulated Per1, Per2, and Binal1 expression in MCF-7 cells. Together, our findings demonstrate that the timing of the circadian clock in reproductive tissues is influenced by the estrous cycle and suggest that fluctuating steroid hormone levels may be responsible, in part, through direct effects on the timing of clock gene expression, (C) 2010 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.steroids.2010.01.007

Zona pellucida protein ZP2 is expressed in the oocyte of Japanese quail (Coturnix japonica) Open Access

Kinoshita Mihoko, Rodler Daniela, Sugiura Kenichi, Matsushima Kayoko, Kansaku Norio, Tahara Kenichi, Tsukada Akira, Ono Hiroko, Yoshimura Takashi, Yoshizaki Norio, Tanaka Ryota, Kohsaka Tetsuya, Sasanami Tomohiro

REPRODUCTION Vol. 139 ( 2 ) page： 359 - 371 2010.2

Publisher：Reproduction

The avian perivitelline layer (PL), a vestment homologous to the zona pellucida (ZP) of mammalian oocytes, is composed of at least three glycoproteins. Our previous studies have demonstrated that the matrix's components, ZP3 and ZPD, are synthesized in ovarian granulosa cells. Another component, ZP1, is synthesized in the liver and is transported to the ovary by blood circulation. In this study, we report the isolation of cDNA encoding quail ZP2 and its expression in the female bird. By RNase protection assay and in situ hybridization, we demonstrate that ZP2 transcripts are restricted to the oocytes of small white follicles (SWF). The expression level of ZP2 decreased dramatically during follicular development, and the highest expression was observed in the SWF.Western blot and immunohistochemical analyses using the specific antibody against ZP2 indicate that the 80 kDa protein is the authentic ZP2, and the immunoreactive ZP2 protein is also present in the oocytes. Moreover, ultrastructural analysis demonstrated that the immunoreactive ZP2 localizes to the zona radiata, the perivitelline space, and the oocyte cytoplasm in the SWF. By means of western blot analysis and immunofluorescence microscopy, we detected a possible interaction of the recombinant ZP2 with ZP3 and that this interaction might lead to the formation of amorphous structure on the cell surface. These results demonstrate for the first time that the avian ZP gene is expressed in the oocyte, and that the ZP2 protein in the oocyte might play a role for the PL formation in the immature follicles of the ovary. © 2010 Society for Reproduction and Fertility.

DOI： 10.1530/REP-09-0222

Photoperiodic Control of TSH-β Expression in the Mammalian Pars Tuberalis has Different Impacts on the Induction and Suppression of the Hypothalamo-Hypopysial Gonadal Axis

Yasuo S., Yoshimura T., Ebihara S., Korf H. -W.

JOURNAL OF NEUROENDOCRINOLOGY Vol. 22 ( 1 ) page： 43 - 50 2010.1

Publisher：Journal of Neuroendocrinology

Seasonal reproduction depends on photoperiod-regulated activation or suppression of the gonadal axis. Recent studies in quail have identified long-day induced . TSH-β expression in the pars tuberalis (PT) as a rapid trigger of gonadal activation. Thyroid-stimulating hormone (TSH) induces type 2 deiodinase (. Dio2) in the ependymal cell layer (EC) of the infundibular recess to stimulate the gonadal axis. A similar mechanism is proposed in sheep and mice, but the experimental data on the temporal patterns of induction and suppression of . TSH-β and . Dio2 expression are incomplete. In the present study, we examined the expression of . TSH-β and . Dio2 in hamsters transferred from short- to long-day conditions for 9 days, and demonstrate the induction of . TSH-β and . Dio2 on day 8 after transition. These data demonstrate the close relationship between . TSH-β and . Dio2 expression in the inductive pathway. The temporal expression of . TSH-β and . Dio2 in the suppressive pathway was also examined by s.c. melatonin injection, which mimics the transition from long to short days. Importantly, . Dio2 expression in the EC is suppressed on day 1 after the onset of injection, whereas . TSH-β expression in the PT was not suppressed until day 10. These data suggest that regulated transcription of . TSH-β is involved in the induction of the gonadal axis in mammals, whereas the suppression of this axis is mediated by different mechanisms. © 2009 The Authors. Journal Compilation © 2009 Blackwell Publishing Ltd.

DOI： 10.1111/j.1365-2826.2009.01936.x

Neuroendocrine mechanism of seasonal reproduction in birds and mammals

Neuroendocrine mechanism of seasonal reproduction in birds and mammals Invited Reviewed Open Access

Yoshimura T

Animal Science Journal Vol. 81 page： 302-410 2010

脊椎動物の季節繁殖の制御機構 Invited

池上啓介、吉村崇

日本生殖内分泌学会雑誌 Vol. 15 page： 55-57 2010

哺乳類の光周性におけるメラトニンの作用機構 Invited Open Access

星野佑太、小野ひろ子、吉村崇

比較内分泌学 Vol. 36 page： 96-101 2010

Deep brain photoreceptors and a seasonal signal transduction cascade in birds Invited Reviewed

Nakane Y, Yoshimura T

Cell and Tissue Research Vol. in press 2010

動物が季節を感じるしくみをさぐる Invited Reviewed

吉村崇

日本の科学者 Vol. 45 page： 54-57 2010

Thyrotropin receptor (TSHR) null mice show methylphenidate-responsive ADHD-like behavioral alternations

Shiho Narusawa, Yuta Hoshino, Akihiro Mouri, Takashi Yoshimura, Toshitaka Nabeshima

JOURNAL OF PHARMACOLOGICAL SCIENCES Vol. 112 page： 229P - 229P 2010

Takashi Yoshimura

ANIMAL SCIENCE JOURNAL Vol. 81 ( 4 ) page： 403 - 410 2010

Language：English Publisher：WILEY-BLACKWELL

In temperate zones, animals use changes in day length as a calendar to time their breeding season. However, the photoreceptive and neuroendocrine mechanisms of seasonal reproduction are considered to differ markedly between birds and mammals. This can be understood from the fact that the eye is the only photoreceptive organ, and melatonin mediates the photoperiodic information in mammals, whereas in birds, photoperiodic information is directly received by the deep brain photoreceptors and melatonin is not involved in seasonal reproduction. Recent molecular and functional genomics analysis uncovered the gene cascade regulating seasonal reproduction in birds and mammals. Long day-induced thyroid stimulating hormone in the pars tuberalis of the pituitary gland regulates thyroid hormone catabolism within the mediobasal hypothalamus. Further, this local thyroid hormone catabolism appears to regulate seasonal gonadotropin-releasing hormone secretion. These findings suggest that although the light input pathway is different between birds and mammals (i.e. light or melatonin), the core mechanisms are conserved in these vertebrates.

DOI： 10.1111/j.1740-0929.2010.00777.x

Localization of circadian clock protein BMAL1 in the photoperiodic signal transduction machinery in Japanese quail. Reviewed International journal

Keisuke Ikegami, Yasuhiro Katou, Kumiko Higashi, Takashi Yoshimura

The Journal of comparative neurology Vol. 517 ( 3 ) page： 397 - 404 2009.11

Language：English Publishing type：Research paper (scientific journal)

The circadian clock is a fundamental property of living organisms and is involved in seasonal (photoperiodic) time measurement. Among vertebrates, birds have multiple circadian pacemakers in the eye, the pineal gland, and the suprachiasmatic nucleus (SCN), and have highly sophisticated photoperiodic mechanisms. However, because the removal of these circadian pacemakers fails to abolish the photoperiodic response, the existence of another "photoperiodic clock" has been suggested. Recent studies have revealed that the mediobasal hypothalamus (MBH) and the adjacent pars tuberalis (PT) of the pituitary gland constitute key components of the photoperiodic signal transduction machinery. In the present study, we generated a polyclonal antibody against the chicken circadian clock protein BMAL1 to examine BMAL1 distribution in the Japanese quail brain by using immunohistochemistry. BMAL1-like immunoreactivity (lir) was confirmed in the pineal gland and the medial SCN, which are critical circadian pacemakers. We also observed strong immunoreactivity in the MBH, including the ependymal cells (ECs), the infundibular nucleus (IN), the median eminence (ME), and the adjacent PT. Furthermore, semiquantitative analysis suggested that BMAL1-lir shows daily fluctuation in these regions. It is possible that circadian clocks in the photoperiodic signal transduction machinery such as the PT and the EC may be involved in the regulation of photoperiodism.

DOI： 10.1002/cne.22165

Comparative analysis of the molecular basis of photoperiodic signal transduction in vertebrates Open Access

Yasuo Shinobu, Yoshimura Takashi

INTEGRATIVE AND COMPARATIVE BIOLOGY Vol. 49 ( 5 ) page： 507 - 518 2009.11

Publisher：Integrative and Comparative Biology

In temperate zones, the reproductive physiology of most vertebrates is controlled by changes in photoperiod. Mechanisms for the regulation of photoperiodic gonadal responses are known to differ between mammals and birds: in mammals, melatonin is the photoperiodic signal messenger, whereas in birds, photoperiodic information is received by deep brain photoreceptors. Recently, the molecular mechanism of photoperiodism has been revealed by studies on Japanese quail, which exhibit a most remarkable responsiveness to photoperiod among vertebrates, and molecular cascades involved in photoperiodism have been elucidated. Long-day stimulus induces expression of the β-subunit of thyroid stimulating hormone (TSH-β) in the pars tuberalis (PT) of the pituitary gland, and TSH derived from the PT regulates reciprocal switching of genes encoding types 2 and 3 deiodinases (Dio2 and Dio3, respectively) in the mediobasal hypothalamus (MBH) by retrograde action. Dio2 locally converts prohormone thyroxine (T4) to bioactive triiodothyronine (T3) in the MBH, which subsequently stimulates the gonadal axis. These events have been confirmed to occur in mammals with seasonal breeding, such as hamsters and sheep, suggesting that similar mechanisms are involved among various vertebrates. In addition, nonphotoperiodic mice also appeared to possess the same molecular mechanisms at the hypothalamo-hypophysial level. It has been noted that melatonin regulates the above-mentioned key genes (Dio2, Dio3, and TSH-β) in mammals, while photoperiod directly regulates these genes in birds. Thus, the input pathway of photoperiod is different between mammals and birds (i.e., melatonin versus light); however, the essential mechanisms are conserved among these vertebrates.

DOI： 10.1093/icb/icp011

Red jungle fowl (Gallus gallus) as a model for studying the molecular mechanism of seasonal reproduction. Reviewed

Usp46 is a quantitative trait gene regulating mouse immobile behavior in the tail suspension and forced swimming tests

Tomida Shigeru, Mamiya Takayoshi, Sakamaki Hirotake, Miura Masami, Aosaki Toshihiko, Masuda Masao, Niwa Minae, Kameyama Tsutomu, Kobayashi Junya, Iwaki Yuka, Imai Saki, Ishikawa Akira, Abe Kuniya, Yoshimura Takashi, Nabeshima Toshitaka, Ebihara Shizufumi

NATURE GENETICS Vol. 41 ( 6 ) page： 688 - 695 2009.6

Ono H, Nakao N, Yamamura T, Kinoshita K, Mizutani M, Namikawa T, Iigo M, Ebihara S, Yoshimura T

Animal science journal = Nihon chikusan Gakkaiho Vol. 80 ( 3 ) page： 328 - 332 2009.6

Melatonin Transmits Photoperiodic Signals through the MT1 Melatonin Receptor Open Access

Yasuo Shinobu, Yoshimura Takashi, Ebihara Shizufumi, Korf Horst-Werner

JOURNAL OF NEUROSCIENCE Vol. 29 ( 9 ) page： 2885 - 2889 2009.3

Molecular and Endocrine Mechanisms of Vertebrate Photoperiodic Response

Yoshimura T.

INTEGRATIVE AND COMPARATIVE BIOLOGY Vol. 49 page： E187 - E187 2009.2

Molecular characterization of egg envelope glycoprotein ZPD in the ovary of Japanese quail (Coturnix japonica) Open Access

Sato Tsukasa, Kinoshita Mihoko, Kansaku Norio, Tahara Kenichi, Tsukada Akira, Ono Hiroko, Yoshimura Takashi, Dohra Hideo, Sasanami Tomohiro

REPRODUCTION Vol. 137 ( 2 ) page： 333 - 343 2009.2

Publisher：Reproduction

The egg envelope surrounding avian oocytes exhibits a three-dimensional network of coarse fibers between the granulosa cells and the oocyte. Our previous studies have demonstrated that one of the matrix's components, ZP3, is synthesized in the ovarian granulosa cells. Another component, ZP1, which is critically involved in triggering the sperm acrosome reaction, is synthesized in the liver. We have previously isolated cDNAs encoding quail ZP3 and ZP1, and we now report the isolation of cDNA encoding quail ZPD. By RNase protection assay and in situ hybridization, we have demonstrated that ZPD transcripts are restricted to the granulosa cells of preovulatory follicles. The expression level of ZPD increased progressively during follicular development, and the highest expression was observed in the largest follicles. Western blot analyses using the specific antibody against ZPD indicate that the 40 kDa protein is the authentic ZPD, and the contents of ZPD protein also increased during follicular development. Moreover, we found that the addition of FSH to the culture media enhances the ZPD secretion in the cultured granulosa cells. Two-dimensional gel electrophoresis revealed the presence of several ZPD isoforms with different pI values ranging from 5.5 to 7. Immunohistochemical analyses indicate that the materials recognized with anti-quail ZPD antibody were accumulated in the egg envelope of large yellow follicles. These results demonstrate the presence of ZPD protein in the egg envelope, and that the amount of ZPD in the egg envelope as well as the mRNA in the cells increases at the latter stages of folliculogenesis. © 2009 Society for Reproduction and Fertility.

DOI： 10.1530/REP-08-0057

Genetic and molecular analysis of wild-derived arrhythmic mice. Reviewed Open Access

Watanabe T, Suzuki T, Ishikawa A, Yokota Y, Ueda HR, Yamada RG, Tei H, Imai S, Tomida S, Kobayashi J, Naito E, Yasuo S, Nakao N, Namikawa T, Yoshimura T, Ebihara S

PloS one Vol. 4 ( 1 ) page： e4301 2009.1

Language：English Publishing type：Research paper (scientific journal) Publisher：PUBLIC LIBRARY SCIENCE

A new circadian variant was isolated by screening the intercross offspring of wild-caught mice (Mus musculus castaneus). This variant was characterized by an initial maintenance of damped oscillations and subsequent loss of rhythmicity after being transferred from light-dark (LD) cycles to constant darkness (DD). To map the genes responsible for the persistence of rhythmicity (circadian ratio) and the length of free-running period (tau), quantitative trait locus (QTL) analysis was performed using F-2 mice obtained from an F-1 cross between the circadian variant and C57BL/6J mice. As a result, a significant QTL with a main effect for circadian ratio (Arrhythmicity; Arrh-1) was mapped on Chromosome (Chr) 8. For tau, four significant QTLs, Short free-running period (Sfp-1) (Chr 1), Sfp-2 (Chr 6), Sfp-3 (Chr 8), Sfp-4 (Chr 11) were determined. An epistatic interaction was detected between Chr 3 (Arrh-2) and Chr 5 (Arrh-3). An in situ hybridization study of clock genes and mouse Period1::luciferase (mPer1::luc) real-time monitoring analysis in the suprachiasmatic nucleus (SCN) suggested that arrhythmicity in this variant might not be attributed to core circadian mechanisms in the SCN neurons. Our strategy using wild-derived variant mice may provide a novel opportunity to evaluate circadian and its related disorders in human that arise from the interaction between multiple variant genes.

DOI： 10.1371/journal.pone.0004301

Identification of the photoperiodic signal transduction pathway regulating seasonal reproduction using the functional genomics approach. Invited Reviewed

Ono H, Nakao N, Yoshimura T

General and Comparative Endocrinology Vol. 163 page： 2-6 2009

Molecular mechanism of seasonal time measurement in vertebrates

Yoshimura Takashi

NEUROSCIENCE RESEARCH Vol. 65 page： S23 - S23 2009

Localization of circadian clock protein in the photoperiodic signal transduction machinery

Ikegami Keisuke, Katou Yasuhiro, Higashi Kumiko, Yoshimura Takashi

NEUROSCIENCE RESEARCH Vol. 65 page： S232 - S232 2009

Effect of dorsal hypothalamic lesion on seasonal reproduction in Japanese quail

Nakane Yusuke, Higashi Kumiko, Iigo Masayuki, Ebihara Shizufumi, Yoshimura Takashi

NEUROSCIENCE RESEARCH Vol. 65 page： S232 - S232 2009

QTL analysis of behavioral despair in mice

Saki Imai, Shigeru Tomida, Takashi Yoshimura, Shizufumi Ebihara

GENES & GENETIC SYSTEMS Vol. 83 ( 6 ) page： 491 - 491 2008.12

Functional genomics of seasonal time measurement

Yoshimura Takashi

GENES & GENETIC SYSTEMS Vol. 83 ( 6 ) page： 530 - 530 2008.12

Identification of a quantitative trait gene underlying behavioral despair using CS mice with abnormal circadian rhythms

Shizufumi Ebihara, Shigeru Tomida, Takayoshi Mamiya, Hirotake Sakamaki, Tsutomu Kameyama, Toshitaka Nabeshima, Junya Kobayashi, Yuka Iwaki, Saki Imai, Akira Ishikawa, Kuniya Abe, Takashi Yoshimura

GENES & GENETIC SYSTEMS Vol. 83 ( 6 ) page： 531 - 531 2008.12

Involvement of thyrotropin in photoperiodic signal transduction in mice Open Access

Ono Hiroko, Hoshino Yuta, Yasuo Shinobu, Watanabe Miwa, Nakane Yusuke, Murai Atsushi, Ebihara Shizufumi, Korf Horst-Werner, Yoshimura Takashi

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Vol. 105 ( 47 ) page： 18238 - 18242 2008.11

Thyroid hormones and seasonal reproductive neuroendocrine interactions Open Access

Nakao Nobuhiro, Ono Hiroko, Yoshimura Takashi

REPRODUCTION Vol. 136 ( 1 ) page： 1 - 8 2008.7

Reorganization of the suprachiasmatic nucleus by photic and non-photic environments Reviewed

Shizufumi Ebihara, Emiko Naito, Tsuyoshi Watanabe, Takashi Yoshimura

SLEEP AND BIOLOGICAL RHYTHMS Vol. 6 ( 2 ) page： 62 - 66 2008.4

Language：English Publishing type：Research paper (scientific journal) Publisher：BLACKWELL PUBLISHING

To better understand alterations in suprachiasmatic nucleus (SCN) physiology by photic and non-photic environments, we analyzed clock gene expression in the mouse SCN by in situ hybridization and real-time monitoring of mPerl::luc bioluminescence. An artificial light : dark : light : dark 7:5:7:S condition induced antiphase oscillation of the clock gene in the dorsomedial-like (DM-like) and the ventrolateral-like (VL-like) subdivisions of the SCN, in parallel with maintaining synchronization between the two sides of the SCN. This antiphase oscillation seems to be responsible for the bimodal rhythms of mPer1 bioluminescence observed in the entire SCN and the components of splitting locomotor activity. A long photoperiod (LP) induced the phase advance of the rhythms of clock gene expression in the caudal SCN relative to those in the rostral SCN. In addition, in the middle SCN, the rhythms of the VL-like subdivision phase-led those in the DM-like subdivision. The mPer1::luc rhythms in the entire coronal slice obtained from the middle SCN exhibited two peaks with a wide peak width under LP conditions. Imaging analysis of the mPerl::luc rhythms revealed wide regional variations in the peak time in the rostral half of the SCN. These variations were not due to alterations in the waveform of a single SCN neuronal rhythm. In CS mice which easily entrain to daily restricted feeding (RF) cycles, the peak width for mPer1::luc bioluminescence rhythms in the SCN markedly increased during the RF schedule under LID conditions. These data in CS mice suggest non-photic cues alter SCN organization and provided a new method to reveal subdivisional changes of the SCN by feeding cues.

DOI： 10.1111/j.1479-8425.2008.00345.x

Reorganization of the suprachiasmatic nucleus coding for day length Reviewed Open Access

Emiko Naito, Tsuyoshi Watanabe, Hajime Tei, Takashi Yoshimura, Shizufumi Ebihara

JOURNAL OF BIOLOGICAL RHYTHMS Vol. 23 ( 2 ) page： 140 - 149 2008.4

Language：English Publishing type：Research paper (scientific journal) Publisher：SAGE PUBLICATIONS INC

In mammals, the suprachiasmatic nucleus (SCN), the circadian pacemaker, receives light information via the retina and functions in the entrainment of circadian rhythms and in phasing the seasonal responses of behavioral and physiological functions. To better understand photoperiod-related alterations in the SCN physiology, we analyzed the clock gene expression in the mouse SCN by performing in situ hybridization and real-time monitoring of the mPer1::luc bioluminescence. Under long photoperiod ( LP) conditions, the expression rhythms of mPer1 and Bma11 in the caudal SCN phase-led those in the rostral SCN; further, within the middle SCN, the rhythms in the ventrolateral (VL)-like subdivision advanced compared with those in the dorsomedial (DM)-like subdivision. The mPer1::luc rhythms in the entire coronal slice obtained from the middle SCN exhibited 2 peaks with a wide peak width under LP conditions. Imaging analysis of the mPer1::luc rhythms in several subdivisions of the rostral, middle, caudal, and horizontal SCN revealed wide regional variations in the peak time in the rostral half of the SCN under LP conditions. These variations were not due to alterations in the waveform of a single SCN neuronal rhythm. Our results indicate that LP conditions induce phase changes in the rhythms in multiple regions in the rostral half of the SCN; this leads to different circadian waveforms in the entire SCN, coding for day length.

DOI： 10.1177/0748730408314572

Molecular evolution of prepro-thyrotropin-releasing hormone in the chicken (Gallus gallus) and its expression in the brain Reviewed

Thyrotrophin in the pars tuberalis triggers photoperiodic response

Nakao Nobuhiro, Ono Hiroko, Yamamura Takashi, Anraku Tsubasa, Takagi Tsuyoshi, Higashi Kumiko, Yasuo Shinobu, Katou Yasuhiro, Kageyama Saburo, Uno Yumiko, Kasukawa Takeya, Iigo Masayuki, Sharp Peter J., Iwasawa Atsushi, Suzuki Yutaka, Sugano Sumio, Niimi Teruyuki, Mizutani Makoto, Namikawa Takao, Ebihara Shizufumi, Ueda Hiroki R., Yoshimura Takashi

NATURE Vol. 452 ( 7185 ) page： 317 - U1 2008.3

脊椎動物が春を感知するしくみをさぐる Invited

吉村崇

蛋白質　核酸　酵素 Vol. 53 page： 1865-1872 2008

鳥類の光周性の機能ゲノミクス Invited

小野ひろ子、中尾暢宏、吉村崇

時間生物学 Vol. 14 page： 2-8 2008

春を告げる甲状腺刺激ホルモン Invited Open Access

中尾暢宏、小野ひろ子、吉村崇

比較内分泌学 Vol. 34 page： 77-82 2008

春を告げる甲状腺刺激ホルモン Invited Open Access

中尾暢宏, 小野ひろ子, 吉村崇

比較内分泌学 Vol. 34 page： 77-82 2008

Positional identification of a quantitative trait gene that controls "behavioral despair" in mice

Shigeru Tomida, Hirotake Sakamaki, Junya Kobayashi, Kuniya Abe, Tsutomu Kameyama, Takayoshi Mamiya, Akira Ishikawa, Takashi Yoshimura, Shizufumi Ebihara

NEUROSCIENCE RESEARCH Vol. 61 page： S70 - S70 2008

Molecular mechanisms of vertebrate photoperiodism

Shizufumi Ebihara, Shinobu Yasuo, Nobuhiro Nakao, Takashi Yoshimura

COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY B-BIOCHEMISTRY & MOLECULAR BIOLOGY Vol. 148 ( 3 ) page： 338 - 338 2007.11

Temporal dynamics of type 2 deiodinase expression after melatonin injections in Syrian hamsters Open Access

Yasuo Shinobu, Yoshimura Takashi, Ebihara Shizufumi, Korf Horst-Werner

ENDOCRINOLOGY Vol. 148 ( 9 ) page： 4385 - 4392 2007.9

Photoperiodic changes in hypothalamic insulin receptor gene expression are regulated by gonadal testosterone

Anraku Tsubasa, Takagi Tsuyoshi, Nakao Nobuhiro, Watanabe Miwa, Yasuo Shinobu, Katou Yasuhiro, Ueda Yukihiro, Murai Atsushi, Ligo Masayuki, Ebihara Shizufumi, Yoshimura Takashi

BRAIN RESEARCH Vol. 1163 page： 86 - 90 2007.8

Circadian clock gene regulation of steroidogenic acute regulatory protein gene expression in preovulatory ovarian follicles

Nakao Nobuhiro, Yasuo Shinobu, Nishimura Atsuko, Yamamura Takashi, Watanabe Tsuyoshi, Anraku Tsubasa, Okano Toshiyuki, Fukada Yoshitaka, Sharp Peter J., Ebihara Shizufumi, Yoshimura Takashi

ENDOCRINOLOGY Vol. 148 ( 7 ) page： 3031 - 3038 2007.7

Aoki, Y., Ono, H., Yasuo, S., Masuda, T., Yoshimura, T., Ebihara, S., Iigo, M., Yanagisawa, T.

Zoological Science Vol. 24 ( 7 ) page： 686 - 692 2007.7

Involvement of transforming growth factor alpha in the photoperiodic regulation of reproduction in birds Open Access

Takagi Tsuyoshi, Yamamura Takashi, Anraku Tsubasa, Yasuo Shinobu, Nakao Nobuhiro, Watanabe Miwa, Iigo Masayuki, Ebihara Shizufumi, Yoshimura Takashi

ENDOCRINOLOGY Vol. 148 ( 6 ) page： 2788 - 2792 2007.6

Bimodal clock gene expression in mouse suprachiasmatic nucleus and peripheral tissues under a 7-hour light and 5-hour dark schedule. Reviewed

Watanabe T, Naito E, Nakao N, Tei H, Yoshimura T, Ebihara S

Journal of biological rhythms Vol. 22 ( 1 ) page： 58 - 68 2007.2

時計遺伝子の進化 Invited

吉村崇, 海老原史樹文

生体の科学 Vol. 57 page： 440-441 2007

Photoperiodic changes in hypothalamic insulin receptor gene expression are regulated by gonadal testosterone Reviewed

Vol. 1163 page： 86-90 2007

Temporal dynamics of type 2 deiodinase expression after melatonin injections in Syrian hamsters Reviewed Open Access

Yasuo S, Yoshimura T, Ebihara S, Korf HW

Endocrinology Vol. 148 page： 4385-4392 2007

Involvement of transforming growth factor alpha in the photoperiodic regulation of reproduction in birds. Reviewed Open Access

Takagi T, Yamamura T, Anraku T, Yasuo S, Nakao N, Watanabe M, Iigo M, Ebihara S, Yoshimura T

Endocrinology Vol. 148 page： 2788-2792 2007

Differential response of type 2 deiodinase gene expression to photoperiod between photoperiodic F344 and nonphotoperiodic Wistar rats Reviewed

Yasuo S, Watanabe M, Iigo M, Nakamura TJ, Watanabe T, Takagi T, Ono H, Ebihara S, Yoshimura T

American Journal of Physiology Vol. 292 page： R1315-R1319 2007

Hypothalamic expression of thyroid hormone-activating and -inactivating enzyme genes in relation to photorefractoriness in birds and mammals Reviewed

Watanabe T, Yamamura T, Watanabe M, Yasuo S, Nakao N, Dawson A, Ebihara S, Yoshimura T

American Journal of Physiology Vol. 292 page： R568-R572 2007

Photoperiodic regulation of seasonal reproduction in birds

T. Yoshimura, S. Yasuo, N. Nakao, T. Yamamura, S. Ebihara

JOURNAL OF ORNITHOLOGY Vol. 147 ( 5 ) page： 65 - 65 2006.8

Overview of avian circadian system

Ebihara S., Yasuo S., Tada A., Yoshimura T.

JOURNAL OF ORNITHOLOGY Vol. 147 ( 5 ) page： 64 - 65 2006.8

Reciprocal switching of type 2 and type 3 deiodinase genes triggers photoperiodic gonadal response in Japanese Quail

S. Yasuo, M. Watanabe, N. Nakao, T. Takagi, S. Ebihara, T. Yoshimura

JOURNAL OF ORNITHOLOGY Vol. 147 ( 5 ) page： 276 - 277 2006.8

Molecular mechanism of the photoperiodic response of gonads in birds and mammals

T Yoshimura

COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY A-MOLECULAR & INTEGRATIVE PHYSIOLOGY Vol. 144 ( 3 ) page： 345 - 350 2006.7

Language：English Publisher：ELSEVIER SCIENCE INC

Appropriate timing of various seasonal processes is crucial to the survival and reproductive success of animals living in temperate regions. When seasonally breeding animals are subjected to annual changes in day length, dramatic changes in neuroendocrine-gonadal activity take place. However, the molecular mechanism underlying the photoperiodic response of gonads remains unknown for all living organisms. It is well known that a circadian clock is somehow involved in the regulation of photoperiodism. Recently, rhythmic expression of circadian clock genes was observed in the mediobasal hypothalamus (MBH) of Japanese quail. The MBH is believed to be the center for photoperiodism. In addition, long-day-induced hormone conversion of the prohormone thyroxine (T-4) to the bioactive triiodothyronine (T-3) by deiodinase in the MBH has been proven to be important to the photoperiodic response of the gonads. Although the regulating mechanism for the photoperiodic response of gonads in birds and mammals has long been considered to be quite different, the long-day-induced expression of the deiodinase gene in the hamster hypothalamus suggests the existence of a conserved regulatory mechanism in avian and mammalian photoperiodism. (c) 2005 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.cbpa.2005.09.009

T3 implantation mimics photoperiodically reduced encasement of nerve terminals by glial processes in the median eminence of Japanese quail

Yamamura T, Yasuo S, Hirunagi K, Ebihara S, Yoshimura T

CELL AND TISSUE RESEARCH Vol. 324 ( 1 ) page： 175 - 179 2006.4

Publisher：Cell and Tissue Research

Photoperiodically generated triiodothyronin (T3) in the mediobasal hypothalamus (MBH) has critical roles in the photoperiodic response of the gonads in Japanese quail. In a previous study, we demonstrated seasonal morphological changes in the neuro-glial interaction between gonadotrophin-releasing hormone (GnRH) nerve terminals and glial endfeet in the median eminence (ME). However, a direct relationship between photoperiodically generated T3 and seasonal neuro-glial plasticity in the ME remained unclear. In the present study, we examined the effect of T3 implantation into the MBH on the neuro-glial interaction in the ME. T 3 implantation caused testicular growth and reduced encasement of nerve terminals in the external zone of the ME. In contrast, no morphological changes were observed in birds given an excessive dose of T3, which did not cause testicular growth. These results support the hypothesis that thyroid hormone regulates photoperiodic GnRH secretion via neuro-glial plasticity in the ME. © Springer-Verlag 2006.

DOI： 10.1007/s00441-005-0126-8

Molecular mechanism of photoperiodic time measurement in the brain of Japanese quail

Peripheral clock gene expression in CS mice with bimodal locomotor rhythms. Reviewed

Watanabe T, Kojima M, Tomida S, Nakamura TJ, Yamamura T, Nakao N, Yasuo S, Yoshimura T, Ebihara S

Neuroscience research Vol. 54 ( 4 ) page： 295 - 301 2006.4

Possible involvement of organic anion transporting polypeptide 1c1 in the photoperiodic response of gonads in birds Open Access

Nakao N, Takagi T, Iigo M, Tsukamoto T, Yasuo S, Masuda T, Yanagisawa T, Ebihara S, Yoshimura T

ENDOCRINOLOGY Vol. 147 ( 3 ) page： 1067 - 1073 2006.3

Molecular analysis of photoperiodic time measurement in birds and mammals

Yoshimura T

JOURNAL OF EXPERIMENTAL ZOOLOGY PART A-COMPARATIVE EXPERIMENTAL BIOLOGY Vol. 305A ( 2 ) page： 196 - 196 2006.2

Long-day suppressed expression of type 2 deiodinase gene in the mediobasal hypothalamus of the saanen goat, a short-day breeder: Implication for seasonal window of thyroid hormone action on reproductive neuroendocrine Open Access

Yasuo S, Nakao N, Ohkura S, Iigo M, Hagiwara S, Goto A, Ando H, Yamamura T, Watanabe M, Watanabe T, Oda SI, Maeda KI, Lincoln GA, Okamura H, Ebihara S, Yoshimura T

ENDOCRINOLOGY Vol. 147 ( 1 ) page： 432 - 440 2006.1

Molecular mechanism of the photoperiodic response of gonads in birds and mammals Invited Reviewed

Yoshimura T

Comparative Biochemistry and Physiology Vol. 144 page： 345-350 2006

Yasuo S, Watanabe M, Iigo M, Yamamura T, Nakao N, Takagi T, Ebihara S, Yoshimura T

CHRONOBIOLOGY INTERNATIONAL Vol. 23 ( 1-2 ) page： 307 - 315 2006

Publisher：Chronobiology International

In most organisms living in temperate zones, reproduction is under photoperiodic control. Although photoperiodic time measurement has been studied in organisms ranging from plants to vertebrates, the underlying molecular mechanism is not well understood. The Japanese quail (Coturnix japonica) represents an excellent model to study this problem because of the rapid and dramatic photoperiodic response of its hypothalamic-pituitary-gonadal axis. Recent investigations of Japanese quail show that long-day-induced type 2 deiodinase (Dio2) expression in the mediobasal hypothalamus (MBH) plays an important role in the photoperiodic gonadal regulation by catalyzing the conversion of the prohormone thyroxine (T4) to bioactive 3,5,3′-triiodothyronine (T3). The T3 content in the MBH is approximately 10-fold higher under long than short days and conditions, and the intracerebroventricular infusion of T3 under short days and conditions mimics the photoperiodic gonadal response. While Dio2 generates active T3 from T4 by outer ring deiodination, type 3 deiodinase (Dio3) catalyzes the conversion of both T3 and T 4 into inactive forms by inner ring deiodination. In contrast to Dio2 expression, Dio3 expression in the MBH is suppressed under the long-day condition. Photoperiodic changes in the expression of both genes during the photoinduction process occur before the changes in the level of luteinizing hormone (LH) secretion, suggesting that the reciprocal changes in Dio2 and Dio3 expression act as gene switches of the photoperiodic molecular cascade to trigger induction of LH secretion. Copyright © Taylor & Francis Group, LLC.

DOI： 10.1080/07420520500521913

Conservation of novel Mahya genes shows the existence of neural functions common between Hymenoptera and Deuterostome

Tsuchimoto M, Yasuo S, Funada M, Aoki M, Sasagawa H, Yoshimura T, Tadauchi O, Cameron SA, Kitagawa Y, Kadowaki T

DEVELOPMENT GENES AND EVOLUTION Vol. 215 ( 11 ) page： 564 - 574 2005.11

Publisher：Development Genes and Evolution

Honeybees have been shown to exhibit cognitive performances that were thought to be specific to some vertebrates. However, the molecular and cellular mechanisms of such cognitive abilities of the bees have not been understood. We have identified a novel gene, Mahya, expressed in the brain of the honeybee, Apis mellifera, and other Hymenoptera. Mahya orthologues are present in Deuterostomes but are absent or highly diverged in nematodes and, intriguingly, in two dipteran insects (fruit fly and mosquito) and Lepidoptera (silk moth). Mahya genes encode novel secretory proteins with a follistatin-like domain (Kazal-type serine/ threonine protease inhibitor domain and EF-hand calcium-binding domain), two immunoglobulin domains, and a C-terminal novel domain. Honeybee Mahya is expressed in the mushroom bodies and antennal lobes of the brain. Zebra fish Mahya orthologues are expressed in the olfactory bulb, telencephalon, habenula, optic tectum, and cerebellum of the brain. Mouse Mahya orthologues are expressed in the olfactory bulb, hippocampus, and cerebellum of the brain. These results suggest that Mahya may be involved in learning and memory and in processing of sensory information in Hymenoptera and vertebrates. Furthermore, the limited existence of Mahya in the genomes of Hymenoptera and Deuterostomes supports the hypothesis that the genes typically represented by Mahya were lost or highly diverged during the evolution of the central nervous system of specific Bilaterian branches under the specific selection and subsequent adaptation associated with different ecologies and life histories. © Springer-Verlag 2005.

DOI： 10.1007/s00427-005-0021-z

Seasonal morphological changes in the neuro-glial interaction between gonadotropin-releasing hormone nerve terminals and glial endfeet in Japanese quail Open Access

The reciprocal switching of two thyroid hormone-activating and -inactivating enzyme genes is involved in the photoperiodic gonadal response of Japanese quail Open Access

Yasuo S, Watanabe M, Nakao N, Takagi T, Follett BK, Ebihara S, Yoshimura T

ENDOCRINOLOGY Vol. 146 ( 6 ) page： 2551 - 2554 2005.6

生物はいかにして季節を読み取っているか？－春を知らせる甲状腺ホルモン－ Invited Open Access

山村崇,安尾しのぶ，中尾暢宏，海老原史樹文，吉村崇

化学と生物 Vol. 43 page： 172-176 2005

脊椎動物の光周性 Invited Open Access

中尾暢宏, 安尾しのぶ, 山村崇, 海老原史樹文, 吉村崇

比較生理生化学 Vol. 22 page： 20-26 2005

脊椎動物における光周性の制御機構 Invited Reviewed Open Access

海老原史樹文, 安尾しのぶ, 吉村崇

生物物理 Vol. 45 page： 185-191 2005

脊椎動物の光周性の分子機構の解明にむけて Invited

吉村崇

時間生物学 Vol. 11 page： 3-7 2005

生物はいかにして季節を読み取っているか？－春を知らせる甲状腺ホルモン－ Invited Open Access

山村崇, 安尾しのぶ, 中尾暢宏, 海老原史樹文, 吉村崇

化学と生物 Vol. 43 page： 172-176 2005

Yamamura T, Hirunagi K, Ebihara S, Yoshimura T

ENDOCRINOLOGY Vol. 145 ( 9 ) page： 4264 - 4267 2004.9

Publisher：Endocrinology

In a previous study we showed that photoperiodically generated T 3 in the hypothalamus is critical for the photoperiodic response of gonads in Japanese quail. The expression of thyroid hormone receptors in the median eminence (ME) suggested that photoperiodically generated T3 acts on the ME. Because thyroid hormone is known to play a critical role in the development and plasticity of the central nervous system, in the present study we have examined ultrastructure of the ME in Japanese quail kept in short-day and long-day environments. Immunoelectron microscopy revealed that GnRH nerve terminals are in close proximity to the basal lamina under long-day conditions, and conventional transmission electron microscopy demonstrated the encasement of the terminals by the endfeet of glia under short-day conditions. These morphological changes may regulate photoperiodic GnRH secretion.

DOI： 10.1210/en.2004-0366

Circadian expression of clock gene in the optic tectum of Japanese quail

Yasuo S, Ebihara S, Yoshimura T

BRAIN RESEARCH Vol. 1005 ( 1-2 ) page： 193 - 196 2004.4

Publisher：Brain Research

The physiological activity of avian optic tectum (TeO) is known to be regulated by the circadian system. In a previous study, we found clock gene expression in the TeO of Japanese quail. Here we report rhythmic expression of the Per2 gene in the stratum griseum et fibrosum (SGF) of the TeO under a light-dark (LD) cycle, constant darkness (DD), and constant light (LL) conditions. However, light pulse did not affect Per2 expression in the TeO. These results suggest that light stimulus and melatonin rhythm are not essential for rhythmic expression of Per2 in the avian TeO in spite of the localization of melatonin receptors and retinal input. © 2004 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.brainres.2004.01.031

Characterization of the two distinct subtypes of metabotropic glutamate receptors from honeybee, Apis mellifera

M Funada, S Yasuo, T Yoshimura, S Ebihara, H Sasagawa, Y Kitagawa, T Kadowaki

NEUROSCIENCE LETTERS Vol. 359 ( 3 ) page： 190 - 194 2004.4

Language：English Publisher：ELSEVIER SCI IRELAND LTD

L-Glutamate is a major neurotransmitter at the excitatory synapses in the vertebrate brain. It is also the excitatory neurotransmitter at neuromuscular junctions in insects, however its functions in their brains remain to be established. We identified and characterized two different subtypes (AmGluRA and AmGluRB) of metabotropic glutamate receptors (mGluRs) from an eusocial insect, honeybee. Both AmGluRA and AmGluRB form homodimers independently on disulfide bonds, and bind [H-3]glutamate with K-D values of 156.7 and 80.7 nM, respectively. AmGluRB is specifically expressed in the brain, while AmGluRA is expressed in the brain and other body parts, suggesting that AmGluRA is also present at the neuromuscular junctions. Both mGluRs are expressed in the mushroom bodies and the brain regions of honeybees, where motor neurons are clustered. Their expression in the brain apparently overlaps, suggesting that they may interact with each other to modulate the glutamatergic neurotransmission. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.neulet.2004.02.004

Expression of IKKα mRNA in the suprachiasmatic nucleus and circadian rhythms of mice lacking IKKα

Photoperiodic regulation of type 2 deiodinase gene in Djungarian hamster: Possible homologies between avian and mammalian photoperiodic regulation of reproduction Open Access

Watanabe M, Yasuo S, Watanabe T, Yamamura T, Nakao N, Ebihara S, Yoshimura T

ENDOCRINOLOGY Vol. 145 ( 4 ) page： 1546 - 1549 2004.4

Photoinducible phase-specific light induction of Cry1 gene in the pars tuberalis of Japanese quail

Yasuo S, Watanabe M, Tsukada A, Takagi T, Iigo M, Shimada K, Ebihara S, Yoshimura T

ENDOCRINOLOGY Vol. 145 ( 4 ) page： 1612 - 1616 2004.4

ウズラ Coturnix japonica Invited

吉村崇

細胞工学 Vol. 23 page： 492-493 2004.4

Circadian expression of clock gene in the optic tectum of Japanese quail

Yasuo S, Ebihara S, Yoshimura T

Brain Research Vol. 1005 page： 193-196 2004.1

鳥類の時計遺伝子と光周性 Invited Reviewed

安尾しのぶ, 渡邊美和, 海老原史樹文, 吉村崇

時間生物学 Vol. 10 page： 35-40 2004

Molecular bases for seasonal reproduction in birds Invited Reviewed Open Access

Yoshimura T

Journal of Poultry Science Vol. 41 page： 251-258 2004

Oral thyroxine administration mimics photoperiodically induced gonadal growth in Japanese quail Reviewed

Animal Science Journal Vol. 75 page： 497-410 2004

鳥類の時計遺伝子と光周性 Invited Reviewed

安尾しのぶ, 渡邊美和, 海老原史樹文, 吉村崇

時間生物学 Vol. 10 page： 35-40 2004

Hayashi N, Yasuo S, Ebihara S, Yoshimura T

BRAIN RESEARCH Vol. 993 ( 1-2 ) page： 217 - 221 2003.12

Publisher：Brain Research

In our previous study, quantitative trait locus (QTL) analysis using mice with abnormal circadian rhythm detected a suggestive QTL, which affects the length of free-running period, on the distal region of Chromosome 19. Among the candidate genes, we have focused on Ikkα gene and found that Ikkα mRNA is expressed in the mammalian circadian pacemaker, the suprachiasmatic nucleus (SCN) in the present study. Expression of Ikkα mRNA in the SCN indicated the possibility that IKKα is involved in the regulation of circadian clock. Therefore, to examine the role of IKKα in the regulation of circadian rhythms, we have further examined wheel-running activity rhythms under light-dark cycle and constant darkness, and circadian response to light. However, we could not detect any statistically significant difference between IKKα+/- mice and wild type mice. Roles of IKKα in the regulation of circadian system remains to be clarified in the future study. © 2003 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.brainres.2003.09.007

Ontogeny of circadian clock gene expression in the pineal and the suprachiasmatic nucleus of chick embryo

Okabayashi N, Yasuo S, Watanabe M, Namikawa T, Ebihara S, Yoshimura T

BRAIN RESEARCH Vol. 990 ( 1-2 ) page： 231 - 234 2003.11

Publisher：Brain Research

Avian circadian rhythms are regulated by a multiple oscillatory system consisting of the pineal, the suprachiasmatic nucleus (SCN) and the eye. In the present study, ontogeny of circadian clock in the pineal and the SCN of chick embryo was examined using Per2 expression as a marker. A daily rhythmicity of Per2 expression was first detectable at embryonic day (ED) 18 in the pineal and at ED 16 in the SCN under light-dark (LD) cycles. The amplitude of the rhythmicity increased during the development. In contrast, little expression was observed during the development in constant darkness. These results suggest that although circadian clock matures by the end of the embryonic life in chicken, LD cycles are required for the expression of the Per2. © 2003 Elsevier B.V. All rights reserved.

DOI： 10.1016/S0006-8993(03)03531-5

Light-induced hormone conversion of T-4 to T-3 regulates photoperiodic response of gonads in birds

T Yoshimura, S Yasuo, M Watanabe, M Iigo, T Yamamura, K Hirunagi, S Ebihara

NATURE Vol. 426 ( 6963 ) page： 178 - 181 2003.11

Language：English Publisher：NATURE PUBLISHING GROUP

Reproduction of many temperate zone birds is under photoperiodic control. The Japanese quail is an excellent model for studying the mechanism of photoperiodic time measurement because of its distinct and marked response to changing photoperiods. Studies on this animal have suggested that the mediobasal hypothalamus (MBH) is an important centre controlling photoperiodic time measurement(1-8). Here we report that expression in the MBH of the gene encoding type 2 iodothyronine deiodinase (Dio2), which catalyses the intracellular deiodination of thyroxine (T-4) prohormone to the active 3,5,3'-triiodothyronine (T-3), is induced by light in Japanese quail. Intracerebroventricular administration of T-3 mimics the photoperiodic response, whereas the Dio2 inhibitor iopanoic acid prevents gonadal growth. These findings demonstrate that light-induced Dio2 expression in the MBH may be involved in the photoperiodic response of gonads in Japanese quail.

DOI： 10.1038/nature02117

Circadian clock genes and photoperiodism: Comprehensive analysis of clock gene expression in the mediobasal hypothalamus, the Suprachiasmatic nucleus, and the pineal gland of Japanese quail under various light schedules Open Access

Yasuo S, Watanabe M, Okabayashi N, Ebihara S, Yoshimura T

ENDOCRINOLOGY Vol. 144 ( 9 ) page： 3742 - 3748 2003.9

Publisher：Endocrinology

In birds, the mediobasal hypothalamus (MBH) including the infundibular nucleus, inferior hypothalamic nucleus, and median eminence is considered to be an important center that controls the photoperiodic time measurement. Here we show expression patterns of circadian clock genes in the MBH, putative suprachiasmatic nucleus (SCN), and pineal gland, which constitute the circadian pacemaker under various light schedules. Although expression patterns of clock genes were different between long and short photoperiod in the SCN and pineal gland, the results were not consistent with those under night interruption schedule, which causes testicular growth. These results indicate that different expression patterns of the circadian clock genes in the SCN and pineal gland are not an absolute requirement for encoding and decoding of seasonal information. In contrast, expression patterns of clock genes in the MBH were stable under various light conditions, which enables animals to keep a steady-state photoinducible phase.

DOI： 10.1210/en.2003-0435

Sleep properties of CS mice with spontaneous rhythm splitting in constant darkness

Ebihara S, Miyazaki S, Sakamaki H, Yoshimura T

BRAIN RESEARCH Vol. 980 ( 1 ) page： 121 - 127 2003.8

Publisher：Brain Research

In mice, genetic differences between inbred strains have been shown for several parameters of sleep and circadian activity rhythms. Our previous studies have demonstrated that CS mice have three remarkable characteristics in the circadian rhythm of locomotor activity: (1) high activity both during the day and night, (2) unstable freerunning period and (3) spontaneous rhythm splitting. In order to characterize sleep properties of CS mice, we compared circadian sleep patterns of CS with those of C57BL/6J and C3H/He mice which have normal circadian activity rhythms. Although C57BL/6J and C3H/He mice exhibited clear daily sleep-wake rhythms in the amount of each sleep parameter (Awake, SWS, PS), CS mice did not show clear rhythms in these parameters. The differences were particularly conspicuous in PS; no apparent day-night differences in the amount of PS, PS counts and PS interval (the interval between successive PS episodes) in CS mice. In addition, the ratio of PS to total sleep time was significantly larger in CS mice than other strains. Of these parameters, the most considerable was PS latency which was extremely short and direct transition from Awake to PS without appearance of SWS frequently occurred in these mice. These results indicate that CS mice may be useful for the understanding of sleep mechanisms and its dysfunction. © 2003 Elsevier B.V. All rights reserved.

DOI： 10.1016/S0006-8993(03)02947-0

Unimodal circadian rhythm in the suprachiasmatic nucleus of behaviorally splitting mice

Watanabe T, Yoshimura T, McMahon DG, Ebihara S

NEUROSCIENCE LETTERS Vol. 345 ( 1 ) page： 49 - 52 2003.7

Publisher：Neuroscience Letters

CS mice exhibit rhythm splitting in constant darkness (DD). To examine the anatomical and physiological bases of this phenomenon, mouse Period1 (mPer1)-driven green fluorescent protein (GFP) mice with rhythm splitting were produced by crossing CS and mPer1::GFP mice. GFP expression in the suprachiasmatic nucleus (SCN) slices showed a clear unimodal rhythm with the highest level at circadian time (CT) 8 or CT12 in splitting and non-splitting GFP mice under DD and no essential differences in the pattern of GFP expression were found between these mice. Moreover, there were no significant differences in the degree of symmetry in the paired rostral, central and caudal SCN between splitting and non-splitting mice. These results indicate that behavioral rhythm splitting in CS mice does not reflect the pattern of clock gene expression in the SCN. © 2003 Elsevier Science Ireland Ltd. All rights reserved.

DOI： 10.1016/S0304-3940(03)00484-1

Quantitative trait locus analysis of abnormal circadian period in CS mice

Ontogeny of circadian clock gene expression in the pineal gland and the suprachiasmatic nucleus of chick embryo

"N. Okabayashi, S. Yasuo, M. Watanabe, T. Namikawa, S. Ebihara, T. Yoshimura"

Brain Research Vol. 990 page： 231-234 2003.1

Expression of IKKalpha mRNA in the suprachiasmatic nucleus and circadian rhythms of mice lacking IKKalpha Reviewed

Hayashi N, Yasuo S, Ebihara S, Yoshimura T

Brain Research Vol. 993 page： 217-221 2003.1

Circadian clock genes and photoperiodism: Comprehensive analysis of clock gene expression in the mediobasal hypothalamus, suprachiasmatic nucleus, and the pineal gland of Japanese quail under various light schedules Reviewed Open Access

Yasuo S, Watanabe M, Okabayashi N, Ebihara S, Yoshimura T

Endocrinology Vol. 144 page： 3742-3748 2003.1

Unimodal circadian rhythm in the suprachiasmatic nucleus of behaviorally splitting mice Reviewed

Watanabe T, Yoshimura T, McMahon D.G., Ebihara S

Neuroscience Letters Vol. 345 page： 49-52 2003.1

Mapping quantitative trait loci affecting circadian photosensitivity in retinally degenerate mice

Yoshimura T, Yokota Y, Ishikawa A, Yasuo SD, Hayashi N, Suzuki T, Okabayashi N, Namikawa T, Ebihara S

JOURNAL OF BIOLOGICAL RHYTHMS Vol. 17 ( 6 ) page： 512 - 519 2002.12

Effect of melatonin administration on qPer2, qPer3, and qClock gene expression in the suprachiasmatic nucleus of Japanese quail Open Access

Yasuo S, Yoshimura T, Bartell PA, Iigo M, Makino E, Okabayashi N, Ebihara S

EUROPEAN JOURNAL OF NEUROSCIENCE Vol. 16 ( 8 ) page： 1541 - 1546 2002.10

ウズラの排卵・放卵周期の制御機構

吉村崇

日本時間生物学会会誌 Vol. 8 page： 38-41 2002.1

QTL解析

"海老原史樹文,鈴木亨,吉村崇,石川明"

分子精神医学 Vol. 2 page： 78-80 2002.1

脊椎動物の概日光受容

"海老原史樹文,吉村崇"

神経研究の進歩 Vol. 45 page： 797-805 2001.10

Suzuki T, Ishikawa A, Yoshimura T, Namikawa T, Abe H, Honma S, Honma K, Ebihara S

MAMMALIAN GENOME Vol. 12 ( 4 ) page： 272 - 277 2001.4

Publisher：Mammalian Genome

CS mice show a free-running period (τ) longer than 24 h and rhythm splitting in constant darkness (DD). These features in behavioral circadian rhythms are distinctive as compared with other inbred strains of mice, which exhibit robust free-running rhythms with τ shorter than 24 h. To identify the genes affecting τ, quantitative trait locus (QTL) analysis was initially conducted by using 289 F2 mice derived from a cross between CS and C57BL/6J strain. A suggestive QTL (LOD = 3.71) with CS allele increasing τ was detected on the distal region of Chromosome (Chr) 19. Next, using 192 F2 mice from a cross between CS and MSM strain, the presence of the QTL on Chr 19 was examined, and we confirmed the QTL at the genome-wide significant level (LOD = 4.61 with 10.4% of the total variance explained). This QTL was named long free-running period (Lfp). Three other suggestive QTLs (LOD = 3.24-4.28) were mapped to the midportion of Chr 12 in (CS×C57BL/6J)F2 mice, and to the proximal and middle region of Chr 19 in (CS×MSM)F2 mice, respectively, of which, CS alleles for two QTLs on Chr 19 have the effect of lengthening τ. None of these QTLs were mapped to the chromosomal regions of previously described QTLs for τ and known clock genes (Clock, mPer1, Bma11, mCry1, mCry2, mTim, and Csnkle).

DOI： 10.1007/s003350010280

Mapping quantitative trait loci for circadian behavioral rhythms in SMXA recombinant inbred strains

Identification of the suprachiasmatic nucleus in birds

Yoshimura T, Yasuo S, Suzuki Y, Makino E, Yokota Y, Ebihara S

AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY Vol. 280 ( 4 ) page： R1185 - R1189 2001.4

Tohru Suzuki, Akira Ishikawa, Masahiko Nishimura, Takashi Yoshimura, Takao Namikawa, Shizufumi Ebihara

Behavior Genetics Vol. 30 ( 6 ) page： 447 - 453 2000.11

Language：English

SM/J and A/J inbred strain of mice have different characteristics in circadian behaviors such as free-running period (τ), phase relationship (ψ) between light-dark cycles and activity rhythms, and amount of wheel-running activity. To determine the genes which affect these behaviors, a quantitative trait locus (QTL) analysis using SMXA recombinant inbred strains derived from SM/J and A/J mice was performed. Concerning τ, two regions on chromosomes (Chrs) 7 and 18 surpassed the genome-wide suggestive level. As for ψ, one suggestive QTL was detected on Chr 7. The QTLs which affect daily activity counts under light-dark cycles and constant darkness were mapped to the same chromosomal regions on Chrs 1 and 17, respectively. The provisional QTLs detected in the present study might be useful for understanding the complex mechanism regulating circadian behaviors.

DOI： 10.1023/A:1010298701251

Molecular analysis of avian circadian clock genes

Yoshimura T, Suzuki Y, Makino E, Suzuki T, Kuroiwa A, Matsuda Y, Namikawa T, Ebihara S

Molecular Brain Research Vol. 78 ( 1-2 ) page： 207 - 215 2000.5

光とサーカディアンリズム

"吉村崇,海老原史樹文"

医学のあゆみ Vol. 190 page： 269-272 1999.1

鳥類の概日リズムの分子機構 Open Access

"吉村崇,海老原史樹文"

日本比較内分泌学会ニュース Vol. 95 page： 34-37 1999.1

Decline of circadian photosensitivity associated with retinal degeneration in CBA/J-rd/rd mice

Yoshimura T, Ebihara S

BRAIN RESEARCH Vol. 779 ( 1-2 ) page： 188 - 193 1998.1

時計遺伝子 Open Access

海老原史樹文、吉村崇

ファルマシア Vol. 34 page： 563-567 1998.1

Chromosomal mapping of the gene encoding serotonin N-acetyltransferase to rat chromosome 10q32.3 and mouse Chromosome 11E2 Reviewed

Takashi Yoshimura, A. Nagabukuro, Y. Matsuda, T. Suzuki, A. Kuroiwa, M. Ligo, T. Namikawa, S. Ebihara

Cytogenetic and Genome Research Vol. 79 ( 3-4 ) page： 172 - 175 1997.1

Language：English Publishing type：Research paper (scientific journal)

Pineal melatonin is produced during the night. Its nocturnal increase regulates circadian rhythms and the photo-periodic reproductive response. Serotonin is acetylated to N-acetylserotonin by serotonin N-acetyltransferase (SNAT) and then methylated to form melatonin by hydroxyindole-O-methyltransferase (HIOMT). The rhythmicity of melatonm synthesis is regulated by the rhythmic activity of SNAT. Most laboratory mice do not have melatonin because of a genetic defect in the activity of SNAT and/or HIOMT. In a previous study using a recombinant inbred strain, we have found that the locus controlling pineal SNAT activity (Nat4) is located on mouse Chromosome 11. Recently, SNAT has been cloned in the rat. In the present study, the gene encoding SNAT was localized, using a rat cDNA fragment, on rat and mouse chromosomes by direct R-banding fluorescence in situ hybridization (FISH). In addition, using molecular linkage analysis with interspecific back-cross mice, a gene encoding SNAT was mapped on a mouse chromosome. The gene encoding SNAT was localized to rat chromosome 10q32.3 and mouse Chromosome 11E2 by FISH. The molecular linkage analysis demonstrated that the gene encoding SNAT maps 1.5 cM distal to DUMit11. The data suggest that Nat4 encodes SNAT. These chromosomal locations are in a region of conserved linkage homology between the two species. © 1997 S. Karger AG, Basel.

DOI： 10.1159/000134713