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
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
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
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
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
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
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.
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
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
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)
News and Views
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
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,
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
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
Am J Physiol 280, R1185-R1189 (2001)
Yoshimura T, Suzuki Y, Makino E, Suzuki T, Kuroiwa A, Matsuda Y, Namikawa T, Ebihara
Molecular analysis of avian circadian clock
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)