論文 - 吉村　崇

Photoperiod decoder 1 regulates seasonal changes in energy metabolism through the growth hormone signaling pathway

Tomoya Nakayama, Taiki Yamaguchi, Michiyo Maruyama, Satoshi Ansai, Makoto Kashima, Romain Fontaine, Christiaan Henkel, Kiyoshi Naruse, Takashi Yoshimura

    2025年2月

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出版者・発行元：Cold Spring Harbor Laboratory  

Seasonal changes in metabolism are crucial for animals to adapt to annual environmental fluctuations. However, the molecular mechanisms underlying these adaptations remain poorly understood. Here, we identified a novel gene,photoperiod decoder 1(phod1), which exhibits a unique bimodal expression pattern under long-day conditions in Japanese medaka fish (Oryzias latipes). Whilephod1is conserved across many vertebrates, except for eutherians, its function remained unknown. Single-cell RNA sequencing analysis revealed thatphod1is predominantly expressed in specific pituitary cells that co-express opsin and circadian clock genes. Transcriptomic analysis usingphod1knockout fish demonstrated thatphod1is essential for photoperiodic regulation of growth hormone. Furthermore, transcriptomic and metabolomic analyses of the liver, the primary target of growth hormone, revealed significant alterations in energy metabolism. Behavioral analysis also showed thatphod1knockout fish exhibited significantly reduced locomotor activity. These findings indicate thatphod1plays a crucial role in seasonal metabolic adaptation through modulation of the growth hormone signaling pathway.

DOI： 10.1101/2025.02.19.638565

The role of circadian clock gene Arntl in the winter depression-like behavior in melatonin-proficient female CBA/N mice

Ren L., Okimura K., Ishikawa A., Kon N., Shimba S., Yoshimura T.

Biochemical and Biophysical Research Communications   734 巻   2024年11月

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出版者・発行元：Biochemical and Biophysical Research Communications  

Seasonal affective disorder (SAD), also known as winter depression, is a subtype of depression typically manifesting in winter. Typical symptoms of SAD, such as an increased need for sleep and carbohydrate cravings associated with increased appetite and weight, are distinct from those of major depression, and the underlying mechanisms of SAD remain unclear. Although laboratory mice are generally considered non-seasonal animals, we observed depression-like behaviors in melatonin-proficient female CBA/N mice maintained under winter-mimicking conditions. Transcriptome analysis of the brains of CBA/N mice maintained under winter- and summer-mimicking conditions revealed changes in the expression of circadian clock genes, including Arntl (also known as Bmal1). We generated Arntl-deficient, melatonin-proficient CBA/N mice using the speed congenic method to examine the role of Arntl in depressive behavior. The tail suspension test in these mice revealed a depressive phenotype. These results suggested that the circadian clock gene Arntl may be involved in winter depression-like behavior.

DOI： 10.1016/j.bbrc.2024.150790

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

Nambo M., Nishiwaki-Ohkawa T., Ito A., Ariki Z.T., Ito Y., Kato Y., Yar M., Yim J.C.H., Kim E., Sharkey E., Kano K., Mishiro-Sato E., Okimura K., Maruyama M., Ota W., Furukawa Y., Nakayama T., Kobayashi M., Horio F., Sato A., Crudden C.M., Yoshimura T.

Communications Medicine   4 巻 ( 1 )   2024年8月

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Communications Medicine  

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

Open Access

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その他リンク： https://www.nature.com/articles/s43856-024-00574-z

STR mutations on chromosome 15q cause thyrotropin resistance by activating a primate-specific enhancer of MIR7-2/MIR1179 査読有り Open Access

Grasberger H., Dumitrescu A.M., Liao X.H., Swanson E.G., Weiss R.E., Srichomkwun P., Pappa T., Chen J., Yoshimura T., Hoffmann P., França M.M., Tagett R., Onigata K., Costagliola S., Ranchalis J., Vollger M.R., Stergachis A.B., Chong J.X., Bamshad M.J., Smits G., Vassart G., Refetoff S.

Nature Genetics   56 巻 ( 5 ) 頁： 877 - 888   2024年5月

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Nature Genetics  

Thyrotropin (TSH) is the master regulator of thyroid gland growth and function. Resistance to TSH (RTSH) describes conditions with reduced sensitivity to TSH. Dominantly inherited RTSH has been linked to a locus on chromosome 15q, but its genetic basis has remained elusive. Here we show that non-coding mutations in a (TTTG)4 short tandem repeat (STR) underlie dominantly inherited RTSH in all 82 affected participants from 12 unrelated families. The STR is contained in a primate-specific Alu retrotransposon with thyroid-specific cis-regulatory chromatin features. Fiber-seq and RNA-seq studies revealed that the mutant STR activates a thyroid-specific enhancer cluster, leading to haplotype-specific upregulation of the bicistronic MIR7-2/MIR1179 locus 35 kb downstream and overexpression of its microRNA products in the participants’ thyrocytes. An imbalance in signaling pathways targeted by these micro-RNAs provides a working model for this cause of RTSH. This finding broadens our current knowledge of genetic defects altering pituitary–thyroid feedback regulation.

DOI： 10.1038/s41588-024-01717-7

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その他リンク： https://www.nature.com/articles/s41588-024-01717-7

FcRY is a key molecule controlling maternal blood IgY transfer to yolks during egg development in avian species 査読有り 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   15 巻   頁： 1305587   2024年

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記述言語：英語   出版者・発行元：Frontiers in Immunology  

Maternal immunoglobulin transfer plays a key role in conferring passive immunity to neonates. Maternal blood immunoglobulin Y (IgY) in avian species is transported to newly-hatched chicks in two steps: 1) IgY is transported from the maternal circulation to the yolk of maturing oocytes, 2) the IgY deposited in yolk is transported to the circulation of the embryo via the yolk sac membrane. An IgY-Fc receptor, FcRY, is involved in the second step, but the mechanism of the first step is still unclear. We determined whether FcRY was also the basis for maternal blood IgY transfer to the yolk in the first step during egg development. Immunohistochemistry revealed that FcRY was expressed in the capillary endothelial cells in the internal theca layer of the ovarian follicle. Substitution of the amino acid residue in Fc region of IgY substantially changed the transport efficiency of IgY into egg yolks when intravenously-injected into laying quail; the G365A mutant had a high transport efficiency, but the Y363A mutant lacked transport ability. Binding analyses of IgY mutants to FcRY indicated that the mutant with a high transport efficiency (G365A) had a strong binding activity to FcRY; the mutants with a low transport efficiency (G365D, N408A) had a weak binding activity to FcRY. One exception, the Y363A mutant had a remarkably strong binding affinity to FcRY, with a small dissociation rate. The injection of neutralizing FcRY antibodies in laying quail markedly reduced IgY uptake into egg yolks. The neutralization also showed that FcRY was engaged in prolongation of half-life of IgY in the blood; FcRY is therefore a multifunctional receptor that controls avian immunity. The pattern of the transport of the IgY mutants from the maternal blood to the egg yolk was found to be identical to that from the fertilized egg yolk to the newly-hatched chick blood circulation, via the yolk sac membrane. FcRY is therefore a critical IgY receptor that regulates the IgY uptake from the maternal blood circulation into the yolk of avian species, further indicating that the two steps of maternal–newly-hatched IgY transfer are controlled by a single receptor.

DOI： 10.3389/fimmu.2024.1305587

DOI： 10.3389/fimmu.2024.1305587

Open Access

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

Nakayama T., Tanikawa M., Okushi Y., Itoh T., Shimmura T., Maruyama M., Yamaguchi T., Matsumiya A., Shinomiya A., Guh Y.J., Chen J., Naruse K., Kudoh H., Kondo Y., Naoki H., Aoki K., Nagano A.J., Yoshimura T.

Proceedings of the National Academy of Sciences of the United States of America   120 巻 ( 52 )   2023年12月

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Proceedings of the National Academy of Sciences of the United States of America  

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

Open Access

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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   9 巻 ( 1 )   2023年12月

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出版者・発行元：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

Open Access

Scopus

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   814 巻   2023年9月

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出版者・発行元：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

Scopus

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

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

PLoS One   18 巻   頁： e0278013   2023年2月

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1371/journal.pone.0278013.

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

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

Gene   846 巻   頁： 146852   2022年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Gene  

Sleep in Drosophila was defined in the year 2000 by using Drosophila Activity Monitor (DAM) system. But DAM is very small tube space and one fly per tube is very limited to analyze for fly social behavior. To overcome such demerits of DAM system, we developed a novel automated sleep and rhythm analysis system (AutoCircaS) which monitors and records any behaviors like social mating, sleep, and circadian rhythm in flies (Drosophila) and small fishes medaka (Oryzias latipes) in free space using the time-lapse (one frame per 10 sec) imaging. AutoCircaS can detect the caffeine-induced insomnia in flies in light–dark (LD) and constant dark (DD) conditions. Thus, using the AutoCircaS, we discovered that Japanese traditional herbal medicines, KyushinKannouGan-ki (KKG), NouKassei (NK) as well as, and Sansoninto, significantly improved caffeine-induced insomnia in flies. The data suggest that AutoCircaS is useful for sleep analysis of small animals and screening of new sedative-hypnotics from many origins.

DOI： 10.1016/j.gene.2022.146852

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

Wang H.t., Miyairi S., Kitamura M., Iizuka K., Asano Y., Yoshimura T., Kon N.

Scientific Reports   12 巻 ( 1 ) 頁： 17325   2022年12月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

Real-time monitoring of cellular temperature responses is an important technique in thermal biology and drug development. Recent study identified that Na+/Ca2+ exchanger (NCX)-dependent Ca2+ influx transduces cold signals to circadian clock in mammalian cultured cells. The finding raised an idea that cellular responses to the cold signals can be analyzed by monitoring of clock gene expression. We found that Per1 and Per2 were up-regulated after culture at 27 °C compared to 37 °C in Rat-1 fibroblasts. In order to monitor cold-Ca2+-dependent transcription in living cells, we developed a luciferase-based real-time reporting system by using Per1 promoter, Per2 promoter, Ca2+/cAMP-response elements (CRE) or NFAT-binding elements. We found that benzyloxyphenyl NCX inhibitor KB-R7943 and SN-6, but not SEA-0400 or YM-244769 inhibited the cold induction of Per2. Our study established a real-time monitoring system for cold Ca2+ signaling which can be applied to evaluation of drugs.

DOI： 10.1038/s41598-022-22166-4

Open Access

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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   12 巻 ( 1 )   2022年12月

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出版者・発行元：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

Open Access

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Prostaglandin E<inf>2</inf> synchronizes lunar-regulated beach spawning in grass puffers 査読有り Open Access

Chen J., Katada Y., Okimura K., Yamaguchi T., Guh Y.J., Nakayama T., Maruyama M., Furukawa Y., Nakane Y., Yamamoto N., Sato Y., Ando H., Sugimura A., Tabata K., Sato A., Yoshimura T.

Current Biology   32 巻 ( 22 ) 頁： 4881 - 4889.e5   2022年10月

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Current Biology  

Many organisms living along the coastlines synchronize their reproduction with the lunar cycle. At the time of spring tide, thousands of grass puffers (Takifugu alboplumbeus) aggregate and vigorously tremble their bodies at the water's edge to spawn. To understand the mechanisms underlying this spectacular semilunar beach spawning, we collected the hypothalamus and pituitary from male grass puffers every week for 2 months. RNA sequencing (RNA-seq) analysis identified 125 semilunar genes, including genes crucial for reproduction (e.g., gonadotropin-releasing hormone 1 [gnrh1], luteinizing hormone β subunit [lhb]) and receptors for pheromone prostaglandin E (PGE). PGE2 is secreted into the seawater during the spawning, and its administration activates olfactory sensory neurons and triggers trembling behavior of surrounding individuals. These results suggest that PGE2 synchronizes lunar-regulated beach-spawning behavior in grass puffers. To further explore the mechanism that regulates the lunar-synchronized transcription of semilunar genes, we searched for semilunar transcription factors. Spatial transcriptomics and multiplex fluorescent in situ hybridization showed co-localization of the semilunar transcription factor CCAAT/enhancer-binding protein δ (cebpd) and gnrh1, and cebpd induced the promoter activity of gnrh1. Taken together, our study demonstrates semilunar genes that mediate lunar-synchronized beach-spawning behavior. Video abstract: [Formula presented]

DOI： 10.1016/j.cub.2022.09.062

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Adenylate kinase 1 overexpression increases locomotor activity in medaka fish 査読有り Open Access

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

PLoS ONE   17 巻 ( 1 January ) 頁： e0257967   2022年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PLoS ONE  

Maintenance of the energy balance is indispensable for cell survival and function. Adenylate kinase (Ak) is a ubiquitous enzyme highly conserved among many organisms. Ak plays an essential role in energy regulation by maintaining adenine nucleotide homeostasis in cells. However, its role at the whole organism level, especially in animal behavior, remains unclear. Here, we established a model using medaka fish (Oryzias latipes) to examine the function of Ak in environmental adaptation. Medaka overexpressing the major Ak isoform Ak1 exhibited increased locomotor activity compared to that of the wild type. Interestingly, this increase was temperature dependent. Our findings suggest that cellular energy balance can modulate locomotor activity.

DOI： 10.1371/journal.pone.0257967

DOI： 10.1371/journal.pone.0257967

Open Access

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Modulation of circadian clock by crude drug extracts used in Japanese Kampo medicine 査読有り 国際誌 Open Access

Zhang M., Kobayashi K., Atsumi H., Katada Y., Nakane Y., Chen J., Nagano R., Kadofusa N., Nishiwaki-Ohkawa T., Kon N., Hirota T., Sato A., Makino T., Yoshimura T.

Scientific Reports   11 巻 ( 1 ) 頁： 21038 - 21038   2021年10月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

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

DOI： 10.1038/s41598-021-00499-w

Open Access

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PubMed

Effects of cryptochrome-modulating compounds on circadian behavioural rhythms in zebrafish 査読有り 国際誌

Iida M., Nakane Y., Yoshimura T., Hirota T.

Journal of Biochemistry   171 巻 ( 5 ) 頁： 501 - 507   2021年9月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Journal of Biochemistry  

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 behavioural rhythms in organisms and suggested species-dependent differences in the effects of isoform-selective CRY-modulating compounds.

DOI： 10.1093/jb/mvab096

DOI： 10.1093/jb/mvab096

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PubMed

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 招待有り

沖村光祐，中山友哉，吉村崇

化学と生物   59 巻   頁： 369 - 376   2021年8月

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担当区分：最終著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Photoperiodic regulation of dopamine signaling regulates seasonal changes in retinal photosensitivity in mice 査読有り 国際誌 Open Access

Okimura K., Nakane Y., Nishiwaki-Ohkawa T., Yoshimura T.

Scientific Reports   11 巻 ( 1 ) 頁： 1843 - 1843   2021年1月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Scientific Reports  

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

DOI： 10.1038/s41598-021-81540-w

Open Access

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PubMed

Light and Hormones in Seasonal Regulation of Reproduction and Mood 招待有り 査読有り

Chen Junfeng, Okimura Kousuke, Yoshimura Takashi

ENDOCRINOLOGY   161 巻 ( 9 )   2020年9月

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出版者・発行元：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

Web of Science

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Genetic analysis of body weight in wild populations of medaka fish from different latitudes 査読有り 国際誌

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

PLOS ONE   15 巻 ( 6 ) 頁： e0234803   2020年6月

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PLoS ONE  

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

Web of Science

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PubMed