Faculty Profiles - YOSHIMURA, Takashi

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

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

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

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

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

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

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

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

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

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

Impaired Circadian Photoentrainment in Opn5-Null Mice

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

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

丸山迪代, 吉村崇

電気泳動 Vol. 63 page： 25 - 29 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

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

中山友哉, 中根右介, 吉村崇

化学と生物 Vol. 57 page： 121 - 128 2019

Ota Wataru, Nakane Yusuke, Hattar Samer, Yoshimura Takashi

ISCIENCE Vol. 6 page： 299 - + 2018.8

Seasonal changes in color perception

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

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