Yoshimura group
Research topics

The appropriate timing of various seasonal processes, such as molting, migration, hibernation, and reproduction, is crucial to the survival of animals living in temperate regions. Reproductive seasonality ensures the birth of young in spring or summer, as is appropriate for survival. Species with a short incubation or gestation period, such as Japanese quail and hamsters, or species with a gestation period of nearly 1 year, such as horses, are long day breeders and their fertile period occurs in the springtime. On the other hand, species with a gestation period of 5-6 months, such as sheep and goats, are short day breeders and their breeding take places in autumn. When seasonally breeding animals are subjected to annual changes in day length, dramatic changes in the neuroendocrine-gonadal activity takes place. However, the molecular mechanism underlying the photoperiodic response of the gonads remains unknown. The goal of our project is to understand the molecular basis of seasonal time measurement in vertebrates.

Birds have evolved especially sophisticated photoperiodic mechanisms, and, among them, the Japanese quail (Coturnix japonica) has proved to be an excellent model for examining photoperiodism. The chain of events, all of which lie within the brain, involves a photoreceptor, a clock (calendar) to measure daylength, and neural circuitry to trigger the increased secretion of gonadotropin releasing hormone (GnRH) and, hence, gonadotropin from the pituitary gland. Many of these functions are thought to involve areas within the mediobasal hypothalamus (MBH).

A circadian clock is known to be involved in the regulation of photoperiodism. Therefore, we have cloned circadian clock genes in the Japanese quail (Yoshimura et al., Mol Brain Res 2000), and observed a rhythmic expression of circadian clock genes in the MBH (Yasuo et al., Endocrinology 2003). This rhythmic expression of circadian clock genes in the MBH appears to be the long-sought clock essential for photoperiodic time measurement.

Thyroid hormones are deeply involved in seasonality. The removal of the thyroid glands in birds and mammals profoundly changes photoperiodic responses, and these responses are restored with replacement therapy. Using Japanese quail as a model species, we have recently uncovered a molecular substrate for these effects. Within the MBH, long daylengths induce the gene for type 2 iodothyronine deiodinase (Dio2). By outer ring deiodination, this enzyme converts the prohormone, thyroxine (T4), into its bioactive form, triiodothyronine (T3). Under long-day conditions, the hypothalamic content of T3 is about 10-fold higher than that under short-day conditions, whereas the intracerebroventricular infusion of T3 induced testicular growth in quail held under nonstimulatory short days (Yoshimura et al., Nature 2003).

Thyroid hormones have a critical involvement in the development, plasticity and function of the central nervous system. Neuroendocrine terminals containing GnRH are thought to be required to contact the pericapillary space so that they can secrete the neurohormone into portal blood. Using electron microscopy, we identified dynamic morphological changes in the GnRH nerve terminals and glial processes. The encasement of the GnRH nerve terminals by the endfeet of glia that was observed in short-day birds was only just detectable in long-day birds (Yamamura et al., 2004). These morphological changes may regulate photoperiodic GnRH secretion.

Although the mechanism regulating the photoperiodic response of gonads in birds and mammals is thought to be quite different, long-day induced Dio2 was also observed in the Djungarian hamster (Watanabe et al., Endocrinology 2004), suggesting the existence of a conserved regulatory mechanism in avian and mammalian photoperiodism. More recently, we reported long-day reduced Dio2 expression in the goat, a short day breeder (Yasuo et al., Endocrinology, in press). This opposite regulation of Dio2 gene in the goat may provide the key to the switching mechanism for long day breeders and short day breeders in future study.

The molecular mechanism of photoperiodic time measurement has been a black box for a long time. Although the results of this project has suggested new avenues for the molecular understanding of photoperiodism, our findings are just the end of the beginning. Recently, chicken draft genome sequence had been reported and a genome-wide comprehensive analysis of avian photoperiodic time measurement is available. Currently, in order to address the complex and dynamic mechanism of photoperiodic time measurement, we are applying a systems biology approach.

Intellectual Merit

Organisms measure day length to adapt their life to the seasonal alteration of the earth, and the mechanism used for this measurement is one of the great mysteries in biology today. Although this phenomenon currently attracts tremendous general interest, its molecular mechanisms remain unknown. This project is intellectually meritorious in that it is the first significant effort to clarify the molecular mechanism of photoperiodic time measurement in vertebrates.

Broader Impacts

Seasonal reproduction is a rate-limiting factor for animal production. The results of this project will contribute to the improvement of animal production and reduce the impact of a food crisis in the future.

Selected Publication

Nakane Y, Ikegami K, Ono H, Yamamoto N, Yoshida S, Hirunagi K, Ebihara S, Kubo Y, Yoshimura T.
A mammalian neural tissue opsin (Opsin 5) is a deep brain photoreceptor in birds.

Proc Natl Acad Sci USA
107, 15264-15268 (2010)
Science Editor's Choice (Aug 20, 2010)

Tomida S, Mamiya T, Sakamaki H, Miura M, Aosaki T, Masuda M, Niwa M, Kameyama T, Kobayashi J, Iwaki Y, Imai S, Ishikawa A, Abe K, Yoshimura T, Nabeshima T, Ebihara S.

Identification of Usp46, encoding a ubiquitin specific peptidase, as a quantitative trait gene regulating mouse immobile behavior in the tail suspension test and forced swimming test.
Nature Genetics 41, 688-695 (2009)

Yasuo S, Yoshimura T, Ebihara S, Korf HW.
Melatonin transmits photoperiodic signals through the MT1 melatonin receptor.
Journal of Neuroscience 29, 2885-2889 (2009)

Ono H, Hoshino Y, Yasuo S, Watanabe M, Nakane Y, Murai A, Ebihara S, Korf HW, Yoshimura T.
Involvement of thyrotropin in photoperiodic signal transduction in mice.

Proc Natl Acad Sci USA
105, 18238-18242 (2008)

Nakao N, Ono H, Yamamura T, Anraku T, Takagi T, Higashi K, Yasuo S, Katou Y, Kageyama S, Uno Y, Kasukawa T, Iigo M, Sharp PJ, Iwasawa A, Suzuki Y, Sugano S, Niimi T, Mizutani M, Namikawa T, Ebihara S, Ueda HR, Yoshimura T.

Thyrotrophin in the pars tuberalis triggers photoperiodic response.

Nature 452, 317-322 (2008)
News & Views
Faculty of 1000 Biology "Exceptional"

Nakao N, Yasuo S, Nishimura A, Yamamura T, Watanabe T, Anraku T, Okano T, Fukada Y, Sharp PJ, Ebihara S, Yoshimura T.

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

Endocrinology 148, 3031-3038 (2007)
News and Views
Faculty of 1000 Biology "Must Read"

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

Involvement of transforming growth factor a in the photoperiodic regulation of reproduction in birds.

Endocrinology 148, 2788-2793 (2007)

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

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

Endocrinology 147, 1067-1073 (2006)
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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 G, Okamura H, Ebihara S, Yoshimura T.

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 axis.

Endocrinology 147, 432-440 (2006)

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

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

Endocrinology 146, 2551-2554 (2005)

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

Photoperiodic regulation of type 2 deiodinase gene in Djungarian hamster: possible homologies between avian and mammalian photoperiodic regulation of reproduction.

Endocrinology 145, 1546-1549 (2004)

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

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

Endocrinology 145, 1612-1616 (2004)

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

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

Endocrinology 145, 4264-4267 (2004)

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

Light-induced hormone conversion of T4 to T3 regulates photoperiodic response of gonads in birds.

Nature 426, 178-181 (2003)

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

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.

Endocrinology 144, 3742-3748 (2003)
News and Views

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

Identification of the suprachiasmatic nucleus in birds.

Am J Physiol 280, R1185-R1189 (2001)

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

Molecular analysis of avian circadian clock genes.

Mol Brain Res 78, 207-215 (2000)

Yoshimura T, Ebihara S.

Spectral sensitivity of photoreceptors mediating phase-shifts of circadian rhythms in retinally degenerate CBA/J (rd/rd) and normal CBA/N (+/+) mice.

J Comp Physiol A 178, 797-802 (1996)