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• W2079304693 abstract "Living organisms detect seasonal changes in day length (photoperiod) [1Dawson A. King V.M. Bentley G.E. Ball G.F. Photoperiodic control of seasonality in birds.J. Biol. Rhythms. 2001; 16: 365-380Crossref PubMed Scopus (752) Google Scholar, 2Ebling F.J. Barrett P. The regulation of seasonal changes in food intake and body weight.J. Neuroendocrinol. 2008; 20: 827-833Crossref PubMed Scopus (104) Google Scholar, 3Revel F.G. Masson-Pévet M. Pévet P. Mikkelsen J.D. Simonneaux V. Melatonin controls seasonal breeding by a network of hypothalamic targets.Neuroendocrinology. 2009; 90: 1-14Crossref PubMed Scopus (72) Google Scholar] and alter their physiological functions accordingly to fit seasonal environmental changes. TSHβ, induced in the pars tuberalis (PT), plays a key role in the pathway that regulates vertebrate photoperiodism [4Nakao N. Ono H. Yamamura T. Anraku T. Takagi T. Higashi K. Yasuo S. Katou Y. Kageyama S. Uno Y. et al.Thyrotrophin in the pars tuberalis triggers photoperiodic response.Nature. 2008; 452: 317-322Crossref PubMed Scopus (383) Google Scholar, 5Nakao N. Ono H. Yoshimura T. Thyroid hormones and seasonal reproductive neuroendocrine interactions.Reproduction. 2008; 136: 1-8Crossref PubMed Scopus (81) Google Scholar]. However, the upstream inducers of TSHβ expression remain unknown. Here we performed genome-wide expression analysis of the PT under chronic short-day and long-day conditions in melatonin-proficient CBA/N mice, in which the photoperiodic TSHβ expression response is preserved [6Ono H. Hoshino Y. Yasuo S. Watanabe M. Nakane Y. Murai A. Ebihara S. Korf H.W. Yoshimura T. Involvement of thyrotropin in photoperiodic signal transduction in mice.Proc. Natl. Acad. Sci. USA. 2008; 105: 18238-18242Crossref PubMed Scopus (210) Google Scholar]. This analysis identified “short-day” and “long-day” genes, including TSHβ, and further predicted the acute induction of long-day genes by late-night light stimulation. We verified this by advancing and extending the light period by 8 hr, which induced TSHβ expression within one day. In the following genome-wide expression analysis under this acute long-day condition, we searched for candidate upstream genes by looking for expression that preceded TSHβ's, and we identified the Eya3 gene. We demonstrated that Eya3 and its partner Six1 synergistically activate TSHβ expression and that this activation is further enhanced by Tef and Hlf. These results elucidate the comprehensive transcriptional photoperiodic response in the PT, revealing the complex regulation of TSHβ expression and unexpectedly rapid response to light changes in the mammalian photoperiodic system. Living organisms detect seasonal changes in day length (photoperiod) [1Dawson A. King V.M. Bentley G.E. Ball G.F. Photoperiodic control of seasonality in birds.J. Biol. Rhythms. 2001; 16: 365-380Crossref PubMed Scopus (752) Google Scholar, 2Ebling F.J. Barrett P. The regulation of seasonal changes in food intake and body weight.J. Neuroendocrinol. 2008; 20: 827-833Crossref PubMed Scopus (104) Google Scholar, 3Revel F.G. Masson-Pévet M. Pévet P. Mikkelsen J.D. Simonneaux V. Melatonin controls seasonal breeding by a network of hypothalamic targets.Neuroendocrinology. 2009; 90: 1-14Crossref PubMed Scopus (72) Google Scholar] and alter their physiological functions accordingly to fit seasonal environmental changes. TSHβ, induced in the pars tuberalis (PT), plays a key role in the pathway that regulates vertebrate photoperiodism [4Nakao N. Ono H. Yamamura T. Anraku T. Takagi T. Higashi K. Yasuo S. Katou Y. Kageyama S. Uno Y. et al.Thyrotrophin in the pars tuberalis triggers photoperiodic response.Nature. 2008; 452: 317-322Crossref PubMed Scopus (383) Google Scholar, 5Nakao N. Ono H. Yoshimura T. Thyroid hormones and seasonal reproductive neuroendocrine interactions.Reproduction. 2008; 136: 1-8Crossref PubMed Scopus (81) Google Scholar]. However, the upstream inducers of TSHβ expression remain unknown. Here we performed genome-wide expression analysis of the PT under chronic short-day and long-day conditions in melatonin-proficient CBA/N mice, in which the photoperiodic TSHβ expression response is preserved [6Ono H. Hoshino Y. Yasuo S. Watanabe M. Nakane Y. Murai A. Ebihara S. Korf H.W. Yoshimura T. Involvement of thyrotropin in photoperiodic signal transduction in mice.Proc. Natl. Acad. Sci. USA. 2008; 105: 18238-18242Crossref PubMed Scopus (210) Google Scholar]. This analysis identified “short-day” and “long-day” genes, including TSHβ, and further predicted the acute induction of long-day genes by late-night light stimulation. We verified this by advancing and extending the light period by 8 hr, which induced TSHβ expression within one day. In the following genome-wide expression analysis under this acute long-day condition, we searched for candidate upstream genes by looking for expression that preceded TSHβ's, and we identified the Eya3 gene. We demonstrated that Eya3 and its partner Six1 synergistically activate TSHβ expression and that this activation is further enhanced by Tef and Hlf. These results elucidate the comprehensive transcriptional photoperiodic response in the PT, revealing the complex regulation of TSHβ expression and unexpectedly rapid response to light changes in the mammalian photoperiodic system. Genome-wide expression data identify “long-day” and “short-day” genes Late-night light stimulation acutely induces Eya3 in the mouse pars tuberalis Eya3 and Six1 synergistically induce TSHβ expression via the Six consensus sequence Activation of the TSHβ promoter is further enhanced by Tef and Hlf via the D box The pars tuberalis (PT) is thought to be responsible for detecting photoperiod, by integrating circadian time and environmental light/dark information [7Reiter R.J. The melatonin rhythm: Both a clock and a calendar.Experientia. 1993; 49: 654-664Crossref PubMed Scopus (907) Google Scholar, 8Lincoln G.A. Andersson H. Loudon A. Clock genes in calendar cells as the basis of annual timekeeping in mammals—a unifying hypothesis.J. Endocrinol. 2003; 179: 1-13Crossref PubMed Scopus (184) Google Scholar, 9Ikegami K. Katou Y. Higashi K. Yoshimura T. Localization of circadian clock protein BMAL1 in the photoperiodic signal transduction machinery in Japanese quail.J. Comp. Neurol. 2009; 517: 397-404Crossref PubMed Scopus (31) Google Scholar]. Recently, a genome-wide expression analysis revealed that the thyroid-stimulating hormone (TSH) pathway triggers photoperiodic responses in the Japanese quail [4Nakao N. Ono H. Yamamura T. Anraku T. Takagi T. Higashi K. Yasuo S. Katou Y. Kageyama S. Uno Y. et al.Thyrotrophin in the pars tuberalis triggers photoperiodic response.Nature. 2008; 452: 317-322Crossref PubMed Scopus (383) Google Scholar, 5Nakao N. Ono H. Yoshimura T. Thyroid hormones and seasonal reproductive neuroendocrine interactions.Reproduction. 2008; 136: 1-8Crossref PubMed Scopus (81) Google Scholar]. In mammals, nocturnal melatonin secretion is thought to carry environmental light/dark information to the PT [10Hoffman R.A. Reiter R.J. Pineal gland: Influence on gonads of male hamsters.Science. 1965; 148: 1609-1611Crossref PubMed Scopus (314) Google Scholar, 11Bittman E.L. Karsch F.J. Hopkins J.W. Role of the pineal gland in ovine photoperiodism: Regulation of seasonal breeding and negative feedback effects of estradiol upon luteinizing hormone secretion.Endocrinology. 1983; 113: 329-336Crossref PubMed Scopus (109) Google Scholar, 12Morgan P.J. Williams L.M. The pars tuberalis of the pituitary: A gateway for neuroendocrine output.Rev. Reprod. 1996; 1: 153-161Crossref PubMed Scopus (83) Google Scholar, 13Goldman B.D. Mammalian photoperiodic system: Formal properties and neuroendocrine mechanisms of photoperiodic time measurement.J. Biol. Rhythms. 2001; 16: 283-301Crossref PubMed Scopus (589) Google Scholar, 14Hazlerigg D. Loudon A. New insights into ancient seasonal life timers.Curr. Biol. 2008; 18: R795-R804Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar], where the melatonin receptor is highly expressed [15Klosen P. Bienvenu C. Demarteau O. Dardente H. Guerrero H. Pévet P. Masson-Pévet M. The mt1 melatonin receptor and RORbeta receptor are co-localized in specific TSH-immunoreactive cells in the pars tuberalis of the rat pituitary.J. Histochem. Cytochem. 2002; 50: 1647-1657Crossref PubMed Scopus (111) Google Scholar]. However, the detailed molecular mechanism that links melatonin signals with TSHβ expression in the PT remains unclear. To identify the upstream inductive mechanism of TSHβ expression, we performed genome-wide expression analyses of the PT under chronic short-day and long-day conditions in melatonin-proficient CBA/N mice, in which the photoperiodic TSHβ expression response is preserved [6Ono H. Hoshino Y. Yasuo S. Watanabe M. Nakane Y. Murai A. Ebihara S. Korf H.W. Yoshimura T. Involvement of thyrotropin in photoperiodic signal transduction in mice.Proc. Natl. Acad. Sci. USA. 2008; 105: 18238-18242Crossref PubMed Scopus (210) Google Scholar] (Experimental Procedures). The data obtained were first analyzed for circadian gene expression (see Supplemental Experimental Procedures available online) because PT contains circadian oscillators [16Guilding C. Hughes A.T. Brown T.M. Namvar S. Piggins H.D. A riot of rhythms: Neuronal and glial circadian oscillators in the mediobasal hypothalamus.Mol. Brain. 2009; 2: 28Crossref PubMed Scopus (130) Google Scholar] (Figure S1A; Supplemental Results and Discussion). We identified 1000 significant 24 hr rhythmic genes in the PT (Figure 1A ; Table S1). The identified genes included several clock and clock-controlled genes (Figure 1B; Table S2; Supplemental Results and Discussion). Their average peak time in the long-day condition was 7.71 hr later than in the short-day condition (Figure 1B), suggesting that circadian clocks in the PT are entrained to the end of a light period. The obtained data were next analyzed to identify “photoperiodic” genes in the PT (Supplemental Experimental Procedures). This photoperiodic expression analysis significantly identified 246 “long-day” genes and 57 “short-day” genes in the PT (Figure 1C; Table S3). The identified genes included TSHβ, which was further confirmed by quantitative PCR (qPCR) and radioisotope (RI) in situ hybridization (Figure 1D). In contrast, TSH α subunit (Cga) and Tac1 [17Dupré S.M. Miedzinska K. Duval C.V. Yu L. Goodman R.L. Lincoln G.A. Davis J.R. McNeilly A.S. Burt D.D. Loudon A.S. Identification of Eya3 and TAC1 as long-day signals in the sheep pituitary.Curr. Biol. 2010; 20: 829-835Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar] did not respond to the photoperiod in the mouse PT (Figures S1B and S1C; see details in Supplemental Results and Discussion). We next examined the timescale of the TSHβ induction after the transition from the short-day to the long-day condition. We transferred mice from the short-day to the long-day condition by delaying lights-off for 8 hr (hereafter, the “delay” condition) and sampled the PTs at zeitgeber time 16 (ZT16; ZT0 was defined as the time of lights-on) because TSHβ is rapidly induced at around ZT16 in the PT of the Japanese quail [4Nakao N. Ono H. Yamamura T. Anraku T. Takagi T. Higashi K. Yasuo S. Katou Y. Kageyama S. Uno Y. et al.Thyrotrophin in the pars tuberalis triggers photoperiodic response.Nature. 2008; 452: 317-322Crossref PubMed Scopus (383) Google Scholar]. However, in contrast to the previously reported immediate induction of TSHβ in the quail, TSHβ expression in the mouse PT increased gradually over the 5 days following the transition from the short- to the long-day condition (Figure 2A ). Because the PT circadian clock was entrained to the lights-off timing (Figure 1B), we speculated that the observed slow dynamics of TSHβ induction in the mouse PT were due to the gradual entrainment of the PT circadian clock. We also hypothesized that the “photoinducible” phase (the circadian time when light stimulation can induce TSHβ expression) is in the subjective (circadian) late night (as defined in the short-day condition), and therefore entrainment over 5 days might be required for full transition of the photoinducible phase to the photoperiod under the long day. To confirm that the PT circadian clock was gradually shifted in this condition, we used a molecular timetable method [18Minami Y. Kasukawa T. Kakazu Y. Iigo M. Sugimoto M. Ikeda S. Yasui A. van der Horst G.T. Soga T. Ueda H.R. Measurement of internal body time by blood metabolomics.Proc. Natl. Acad. Sci. USA. 2009; 106: 9890-9895Crossref PubMed Scopus (207) Google Scholar, 19Ueda H.R. Chen W. Minami Y. Honma S. Honma K. Iino M. Hashimoto S. Molecular-timetable methods for detection of body time and rhythm disorders from single-time-point genome-wide expression profiles.Proc. Natl. Acad. Sci. USA. 2004; 101: 11227-11232Crossref PubMed Scopus (91) Google Scholar], which can measure circadian phase from the expression pattern of clock and clock-controlled genes with a single-time-point sample (Supplemental Experimental Procedures). We found that the PT circadian time was gradually shifted over 5 days (Figure 2B). We also noted that the circadian time in the PT correlated well with the induction of TSHβ expression (Figure 2C; r2 = 0.7569), consistent with the hypothesis. Based on these findings, we plotted the measured circadian time and the hypothesized photoinducible phase (i.e., the circadian late-night period) over the 5 days after the shift and superimposed it on the photoperiod (Figure 2D). This plot showed that TSHβ expression was not induced on the first day as a result of the mismatch between the hypothetical photoinducible phase of the PT (Figure 2D, orange-outlined box) and the photoperiod (Figure 2D, day 1), whereas TSHβ expression was strongly induced on the fifth day because of the match between the hypothetical photoinducible phase and the photoperiod, after gradual entrainment of the PT over 5 days (Figure 2D, day 5). This result supports our hypothesis that the photoinducible phase is in the circadian late-night period. Furthermore, this hypothesis also predicted that TSHβ expression would be strongly induced on the first day in an alternative long-day condition in which the lights-on timing was advanced by 8 hr (hereafter, the “advance” condition). To verify this prediction, we examined TSHβ expression in the PT under the advance condition, and we found that it increased immediately (Figure 2E; Figure S1D). RI in situ hybridization also confirmed this immediate TSHβ expression (Figure 2E, right panels). On the other hand, TSHβ expression was not induced in the delay condition (Figure 2E, left-bottom panel; Figure S1D). These findings suggest that the mouse PT has a photoinducible phase during subjective late night and that light stimulation occurring in the late night can induce TSHβ expression immediately, i.e., within one day. Given the rapid induction of TSHβ, we reasoned that a genome-wide expression analysis in the advance and delay conditions might allow us to identify the the upstream inductive mechanism of the TSHβ pathway. Therefore, we performed a second set of genome-wide expression analyses under these acute long-day conditions (Experimental Procedures). The data obtained were then analyzed to extract “acute long-day” genes expressed in the PT (Supplemental Experimental Procedures). This expression analysis identified 34 acute long-day genes in the PT (Figure 3A ; Table S4), which included several transcription factors; Eya3, Rorβ, Maff, Crem, and Hdac4 (Figure S1D). We focused on Eya3 as a putative upstream activator of TSHβ expression because Crem and Hdac4 encode transcriptional repressors [20Jeong B.C. Hong C.Y. Chattopadhyay S. Park J.H. Gong E.Y. Kim H.J. Chun S.Y. Lee K. Androgen receptor corepressor-19 kDa (ARR19), a leucine-rich protein that represses the transcriptional activity of androgen receptor through recruitment of histone deacetylase.Mol. Endocrinol. 2004; 18: 13-25Crossref PubMed Scopus (56) Google Scholar, 21Gordon J.W. Pagiatakis C. Salma J. Du M. Andreucci J.J. Zhao J. Hou G. Perry R.L. Dan Q. Courtman D. et al.Protein kinase A-regulated assembly of a MEF2⋅HDAC4 repressor complex controls c-Jun expression in vascular smooth muscle cells.J. Biol. Chem. 2009; 284: 19027-19042Crossref PubMed Scopus (55) Google Scholar] and because Rorβ and Maff could not activate the 7.7 kbp promoter of TSHβ (Figures S2A and S2B). We first confirmed the acute induction of Eya3 expression in the PT under the advance condition via qPCR and RI in situ hybridization (Figure 3B; Supplemental Results and Discussion). Eya3 is one of four mammalian homologs (Eya1–4) of eya [22Xu P.X. Woo I. Her H. Beier D.R. Maas R.L. Mouse Eya homologues of the Drosophila eyes absent gene require Pax6 for expression in lens and nasal placode.Development. 1997; 124: 219-231Crossref PubMed Google Scholar, 23Borsani G. DeGrandi A. Ballabio A. Bulfone A. Bernard L. Banfi S. Gattuso C. Mariani M. Dixon M. Donnai D. et al.EYA4, a novel vertebrate gene related to Drosophila eyes absent.Hum. Mol. Genet. 1999; 8: 11-23Crossref PubMed Scopus (121) Google Scholar], a transcriptional coactivator involved in fly eye development [24Bonini N.M. Leiserson W.M. Benzer S. The eyes absent gene: Genetic control of cell survival and differentiation in the developing Drosophila eye.Cell. 1993; 72: 379-395Abstract Full Text PDF PubMed Scopus (442) Google Scholar, 25Bonini N.M. Leiserson W.M. Benzer S. Multiple roles of the eyes absent gene in Drosophila.Dev. Biol. 1998; 196: 42-57Crossref PubMed Scopus (98) Google Scholar]. Eya family members form a complex with a DNA-binding factor of the Six family and a corepressor of the Dach family. Six-Eya-Dach genetic interactions are reported to regulate the transcriptional activation and repression of target genes. Of the Eya, Six, and Dach families, we found that the Eya3 and Six1 mRNAs were highly expressed in the PT under the long-day condition whereas the others were weakly or barely expressed (Figure 4A ). We therefore examined whether Eya3 and Six1 activate the TSHβ promoter. The transient transfection of Eya3 or Six1 increased the TSHβ promoter activity only slightly, whereas their cotransfection synergistically increased its activation (Figure 4B). In contrast, Eya3 and Six1 did not activate the SV40 promoter. We also found that shorter versions of the TSHβ promoter (Figure 4C) were also synergistically activated by Eya3 and Six1 (Figure 4B). We thus used the shortest version of the TSHβ promoter (0.1 kbp) in the following experiments unless otherwise indicated. We also confirmed that Eya3 increased TSHβ promoter activity in a dose-dependent manner when it was expressed alone or with Six1 (Figure 4D; Figure S2C; Supplemental Results and Discussion). It has been reported that Six and Eya can activate their target genes through different consensus sequences for Six binding (MEF3 site, see [26Spitz F. Demignon J. Porteu A. Kahn A. Concordet J.P. Daegelen D. Maire P. Expression of myogenin during embryogenesis is controlled by Six/sine oculis homeoproteins through a conserved MEF3 binding site.Proc. Natl. Acad. Sci. USA. 1998; 95: 14220-14225Crossref PubMed Scopus (183) Google Scholar, 27Li X. Oghi K.A. Zhang J. Krones A. Bush K.T. Glass C.K. Nigam S.K. Aggarwal A.K. Maas R. Rose D.W. Rosenfeld M.G. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis.Nature. 2003; 426: 247-254Crossref PubMed Scopus (504) Google Scholar]; So site, see [27Li X. Oghi K.A. Zhang J. Krones A. Bush K.T. Glass C.K. Nigam S.K. Aggarwal A.K. Maas R. Rose D.W. Rosenfeld M.G. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis.Nature. 2003; 426: 247-254Crossref PubMed Scopus (504) Google Scholar, 28Pauli T. Seimiya M. Blanco J. Gehring W.J. Identification of functional sine oculis motifs in the autoregulatory element of its own gene, in the eyeless enhancer and in the signalling gene hedgehog.Development. 2005; 132: 2771-2782Crossref PubMed Scopus (76) Google Scholar, 29Giordani J. Bajard L. Demignon J. Daubas P. Buckingham M. Maire P. Six proteins regulate the activation of Myf5 expression in embryonic mouse limbs.Proc. Natl. Acad. Sci. USA. 2007; 104: 11310-11315Crossref PubMed Scopus (83) Google Scholar]). Therefore, we searched for Six consensus sequences in the 0.1 kbp TSHβ promoter and found one MEF3 site (+1) and two So sites (−45 and −52) upstream of the transcription start site (TSS). These MEF3 and So sites in the TSHβ promoter are highly conserved among vertebrates (Figure 4C). We first deleted and mutated the one MEF3 site in the TSHβ promoter and found that it was dispensable for the Eya3-Six-dependent activation of the TSHβ promoter (Figure 4E). We then sequentially deleted the two So sites (Figure 4C, So1 and So2). Although deletion of the So2 site did not affect the Eya3-Six-dependent activation of the TSHβ promoter, deletion of the So1 site significantly decreased the change elicited by the Eya3-Six-dependent activation (Figure 4F). These results indicate that the So1 site is essential for the full activation of the TSHβ promoter by the Eya3-Six1 complex. Because Tef can increase TSHβ promoter activity [30Drolet D.W. Scully K.M. Simmons D.M. Wegner M. Chu K.T. Swanson L.W. Rosenfeld M.G. TEF, a transcription factor expressed specifically in the anterior pituitary during embryogenesis, defines a new class of leucine zipper proteins.Genes Dev. 1991; 5: 1739-1753Crossref PubMed Scopus (207) Google Scholar], we also examined the contribution of Tef and its family member Hlf to the 0.1 kbp TSHβ promoter. We found that Tef or Hlf synergistically increased the luciferase activity of the TSHβ promoter when cotransfected with Eya3 and Six1 (Figures S2D–S2J; see details in Supplemental Results and Discussion). In this study, genome-wide expression analyses of the mouse PT revealed that TSHβ and Eya3 expression are induced by late-night light stimulation. Because these expression data might include potentially important factors besides Eya3 and TSHβ, we have made them publicly available (http://photoperiodism.brainstars.org/). We further demonstrated that Eya3 and its partner Six1 are expressed in the mouse PT and synergistically activate TSHβ expression through an So site in the TSHβ promoter. This activation is further enhanced by Tef and Hlf through a D box close to the So site. Because previous reports described Eya3 induction in the PT under long-day conditions in birds [4Nakao N. Ono H. Yamamura T. Anraku T. Takagi T. Higashi K. Yasuo S. Katou Y. Kageyama S. Uno Y. et al.Thyrotrophin in the pars tuberalis triggers photoperiodic response.Nature. 2008; 452: 317-322Crossref PubMed Scopus (383) Google Scholar, 5Nakao N. Ono H. Yoshimura T. Thyroid hormones and seasonal reproductive neuroendocrine interactions.Reproduction. 2008; 136: 1-8Crossref PubMed Scopus (81) Google Scholar] and sheep [17Dupré S.M. Miedzinska K. Duval C.V. Yu L. Goodman R.L. Lincoln G.A. Davis J.R. McNeilly A.S. Burt D.D. Loudon A.S. Identification of Eya3 and TAC1 as long-day signals in the sheep pituitary.Curr. Biol. 2010; 20: 829-835Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar], its induction under long-day conditions appears to be an evolutionarily conserved molecular mechanism in the photoperiodism of vertebrates. Among the remaining challenges is the in vivo functional analysis of Eya3-dependent induction of TSHβ expression. Based on these and previous findings, we propose the following hypothetical model for a gradual transition over months from short-day to long-day conditions in the natural environment. As the photoperiod is gradually extended to completely cover the photoinducible phase (the subjective late night, determined in the short-day condition), Eya3 is gradually induced, which triggers TSHβ expression in the PT under natural conditions. These natural and relatively slow expression dynamics can be speeded up by artificial light stimulation at subjective late night, which acutely induces Eya3 expression. This artificial situation reveals that the mammalian photoperiodic system has unexpectedly rapid dynamics and indicates that the PT of CBA/N mice is an ideal model system for elucidating the remaining molecular mechanisms of photoperiodism (Supplemental Results and Discussion). Identifying the upstream inducer of the acute Eya3 elevation as well as elucidating the signal transduction cascade from the melatonin receptor to Eya3 expression will provide further insights into photoperiodism. Male CBA/N mice (Japan SLC, Shizuoka, Japan), which have normal retinas (Supplemental Results and Discussion), were purchased 3 weeks after birth. For chronic long-day and short-day experiments, mice were first housed under short-day conditions (light:dark = 8:16 hr, ZT0 = lights-on, ZT8 = lights-off, 400 lux), given food and water ad libitum, and maintained under these short-day conditions for 3 weeks. The mice were then separated into two groups. One group was maintained under the short-day conditions and the other was housed under long-day conditions (light:dark = 16:8 hr, ZT0 = lights-on, ZT16 = lights-off, 400 lux) for 2 weeks. Mice in both groups were sacrificed and their PTs were sampled every 4 hr for 1 day, starting at ZT0. For the acute long-day experiments, mice were first housed under short-day conditions for 3 weeks as described above and then separated into two groups. In one, the lights-on timing was advanced by 8 hr (advance condition), and in the other, the lights-off timing was delayed by 8 hr (delay condition). In both cases, photoperiod was extended by 8 hr. PTs from both groups were obtained every 4 hr for 1 day, starting at the lights-on time (ZT16 in the advance condition and ZT0 in the delay condition, when ZT was defined in the short-day condition). This study was performed in compliance with the Rules and Regulations of the Animal Care and Use Committee, Kinki University School of Medicine, and carefully followed the Guide for the Care and Use of Laboratory Animals, Kinki University School of Medicine. Mice were also carefully kept and handled according to the RIKEN Regulations for Animal Experiments. Slices (0.5 mm thick) of the brain of CBA/N mice were cut on a mouse brain matrix (Neuroscience, Inc., Tokyo) and frozen, and the PT was punched out with a microdissecting needle (gauge 0.5 mm) under a stereomicroscope. The samples included a small amount of the surrounding tissue, such as the median eminence and ependymal cells. We sampled 25 mice at each time point. This entire procedure was repeated twice (n = 2) to obtain experimental replicates. Total RNA was prepared from the pooled PT samples obtained at each time point under each condition using TRIzol reagent (GIBCO). cDNA synthesis and cRNA labeling reactions were performed as described previously [31Ueda H.R. Matsumoto A. Kawamura M. Iino M. Tanimura T. Hashimoto S. Genome-wide transcriptional orchestration of circadian rhythms in Drosophila.J. Biol. Chem. 2002; 277: 14048-14052Crossref PubMed Scopus (234) Google Scholar]. Affymetrix high-density oligonucleotide arrays for Mus musculus (GeneChip Mouse Genome 430 2.0) were hybridized, stained, and washed according to the Expression Analysis Technical Manual (Affymetrix). The expression values were summarized by the robust multiarray analysis method [32Irizarry R.A. Bolstad B.M. Collin F. Cope L.M. Hobbs B. Speed T.P. Summaries of Affymetrix GeneChip probe level data.Nucleic Acids Res. 2003; 31: e15Crossref PubMed Scopus (4014) Google Scholar]. The microarray data are available at the NCBI Gene Expression Omnibus (GSE24775) or at our website (http://photoperiodism.brainstars.org/). We thank Joseph Takahashi for mPer2Luc mice and Yoichi Minami and Masayuki Iigo for helpful discussions. We also thank Junko Sakai and Yoko Sakakida for technical assistance. Some calculations were performed by the RIKEN Super Combined Cluster. This work was performed as a part of the Genome Network Project of the Ministry of Education, Culture, Sports, Science and Technology of Japan (H.R.U.). This research was supported by an intramural Grant-in-Aid from the RIKEN Center for Developmental Biology (H.R.U.), the RIKEN President's Fund (H.R.U.), and a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Y.S.). Microarray data reported herein have been deposited in the NCBI Gene Expression Omnibus with the accession number GSE24775. Download .pdf (1.48 MB) Help with pdf files Document S1. Supplemental Results and Discussion, Two Figures, and Supplemental Experimental Procedures Download .xls (.77 MB) Help with xls files Document S2. Four Tables A Molecular Switch for Photoperiod Responsiveness in MammalsDardente et al.Current BiologyDecember 2, 2010In BriefSeasonal synchronization based on day length (photoperiod) allows organisms to anticipate environmental change. Photoperiodic decoding relies on circadian clocks, but the underlying molecular pathways have remained elusive [1]. In mammals and birds, photoperiodic responses depend crucially on expression of thyrotrophin β subunit RNA (TSHβ) in the pars tuberalis (PT) of the pituitary gland [2–4]. Now, using our well-characterized Soay sheep model [2], we describe a molecular switch governing TSHβ transcription through the circadian clock. Full-Text PDF Open Archive" @default.
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• W2079304693 title "Acute Induction of Eya3 by Late-Night Light Stimulation Triggers TSHβ Expression in Photoperiodism" @default.
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