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• W2032656475 abstract "A program of stringently-regulated gene expression is thought to be a fundamental component of the circadian clock. Although recent work has implicated a role for E-box-dependent transcription in circadian rhythmicity, the contribution of other enhancer elements has yet to be assessed. Here, we report that cells of the suprachiasmatic nuclei (SCN) exhibit a prominent circadian oscillation in cAMP response element (CRE)-mediated gene expression. Maximal reporter gene expression occurred from late-subjective night to mid-subjective day. Cycling of CRE-dependent transcription was not observed in other brain regions, including the supraoptic nucleus and piriform cortex. Levels of the phospho-active form of the transcription factor CREB (P-CREB) varied as a function of circadian time. Peak P-CREB levels occurred during the mid- to late-subjective night. Furthermore, photic stimulation during the subjective night, but not during the subjective day, triggered a marked increase in CRE-mediated gene expression in the SCN. Reporter gene experiments showed that activation of the p44/42 mitogen-activated protein kinase signaling cascade is required for Ca2+-dependent stimulation of CRE-mediated transcription in the SCN. These findings reveal the CREB/CRE transcriptional pathway to be circadian-regulated within the SCN, and raise the possibility that this pathway provides signaling information essential for normal clock function. A program of stringently-regulated gene expression is thought to be a fundamental component of the circadian clock. Although recent work has implicated a role for E-box-dependent transcription in circadian rhythmicity, the contribution of other enhancer elements has yet to be assessed. Here, we report that cells of the suprachiasmatic nuclei (SCN) exhibit a prominent circadian oscillation in cAMP response element (CRE)-mediated gene expression. Maximal reporter gene expression occurred from late-subjective night to mid-subjective day. Cycling of CRE-dependent transcription was not observed in other brain regions, including the supraoptic nucleus and piriform cortex. Levels of the phospho-active form of the transcription factor CREB (P-CREB) varied as a function of circadian time. Peak P-CREB levels occurred during the mid- to late-subjective night. Furthermore, photic stimulation during the subjective night, but not during the subjective day, triggered a marked increase in CRE-mediated gene expression in the SCN. Reporter gene experiments showed that activation of the p44/42 mitogen-activated protein kinase signaling cascade is required for Ca2+-dependent stimulation of CRE-mediated transcription in the SCN. These findings reveal the CREB/CRE transcriptional pathway to be circadian-regulated within the SCN, and raise the possibility that this pathway provides signaling information essential for normal clock function. In mammals, the suprachiasmatic nuclei (SCN) 1The abbreviations used are: SCN, suprachiasmatic nuclei; CRE, cAMP response element; CREB, CRE-binding protein; P-CREB, phospho-active CREB; MAPK, mitogen-activated protein kinase; PKA, protein kinase A; L, light; D, dark; CT, circadian time; PBS, phosphate-buffered saline; PBST, PBS with Triton X-100; RHT, retinohypothalamic tract; ERK, extracellular signal-regulated kinase; D/N, dominant negative; DM, dissociation medium; MEK, MAPK kinase. 1The abbreviations used are: SCN, suprachiasmatic nuclei; CRE, cAMP response element; CREB, CRE-binding protein; P-CREB, phospho-active CREB; MAPK, mitogen-activated protein kinase; PKA, protein kinase A; L, light; D, dark; CT, circadian time; PBS, phosphate-buffered saline; PBST, PBS with Triton X-100; RHT, retinohypothalamic tract; ERK, extracellular signal-regulated kinase; D/N, dominant negative; DM, dissociation medium; MEK, MAPK kinase. of the hypothalamus contain a circadian oscillator that functions as the major biological clock (1Hastings M.H. Best J.D. Ebling F.J. Maywood E.S. McNulty S. Schurov I. Selvage D. Sloper P. Smith K.L. Brain Res. 1996; 111: 147-174Crossref Google Scholar, 2Miller J.D. Morin L.P. Schwartz W.J. Moore R.Y. Sleep. 1996; 19: 641-667Crossref PubMed Scopus (155) Google Scholar, 3van den Pol A.N. Dudek F.E. Neurosci. 1993; 56: 793-811Crossref PubMed Scopus (149) Google Scholar). The biorhythm generated by the SCN allows an organism to predict and coordinate its daily physiological processes to an approximate 24-h period. If the SCN are lesioned, there is a loss of physiological and behavioral circadian rhythms (4Moore R.Y. Eichler V.B. Brain Res. 1972; 42: 201-206Crossref PubMed Scopus (1604) Google Scholar, 5Stephan F.K. Zucker I. Proc. Natl. Acad. Sci. U. S. A. 1972; 69: 1583-1586Crossref PubMed Scopus (1547) Google Scholar). The most effective regulator of the endogenous clock is light; endogenous clock rhythmicity is entrained to the environmental light cycle by photic cues conveyed from the eyes to the SCN via the retinohypothalamic tract (RHT) (6Moore R.Y. Lenn N.J. J. Comp. Neurol. 1972; 146: 1-14Crossref PubMed Scopus (1015) Google Scholar). For example, if an animal receives a light flash during the dark phase of the day/night light cycle, the circadian rhythm is reset, or phase-shifted (7Daan S. Pittendrigh C.S. J. Comp. Physiol. 1976; 106: 253-266Crossref Scopus (254) Google Scholar). Light-induced phase-shifting results from the synaptic release of glutamate from the RHT onto the SCN (8Colwell C.S. Foster R.G. Menaker M. Brain Res. 1991; 554: 105-110Crossref PubMed Scopus (117) Google Scholar, 9Colwell C.S. Menaker M. J. Biol. Rhythms. 1992; 7: 125-136Crossref PubMed Scopus (158) Google Scholar, 10Liou S.Y. Shibata S. Iwasaki K. Ueki S. Brain Res. Bull. 1986; 16: 527-531Crossref PubMed Scopus (157) Google Scholar). Entrainment of the clock by light is thought to involve changes in gene expression. In support of this, several studies have shown that immediate early gene induction is triggered by light (11Kornhauser J.M. Nelson D.E. Mayo K.E. Takahashi J.S. Neuron. 1990; 5: 127-134Abstract Full Text PDF PubMed Scopus (455) Google Scholar, 12Kornhauser J.M. Nelson D.E. Mayo K.E. Takahashi J.S. Science. 1992; 255: 1581-1584Crossref PubMed Scopus (196) Google Scholar, 13Rusak B. Robertson H.A. Wisden W. Hunt S.P. Science. 1990; 248: 1237-1240Crossref PubMed Scopus (478) Google Scholar).Recent work has revealed important information about specific proteins and transcriptional events essential for circadian rhythmicity. For example, CLOCK and BMAL1 proteins heterodimerize to form a transcription factor that binds the E-box enhancer element, resulting in mper1 gene expression (14Gekakis N. Staknis D. Nguyen H.B. Davis F.C. Wilsbacher L.D. King D.P. Takahashi J.S. Weitz C.J. Science. 1998; 280: 1564-1569Crossref PubMed Scopus (1537) Google Scholar). In Drosophila, PER/TIM dimers negatively regulate CLOCKdependent transcription (15Darlington T.K. Wager-Smith K. Ceriani M.F. Staknis D. Gekakis N. Steeves T.D.L. Weitz C.J. Takahashi J.S. Kay S.A. Science. 1998; 280: 1599-1603Crossref PubMed Scopus (685) Google Scholar), thus forming a negative feedback loop. Mutations of any of these genes disrupts circadian rhythmicity (16Vitaterna M.H. King D.P. Chang A.M. Kornhauser J.M. Lowrey P.L. McDonald J.D. Dove W.F. Pinto L.H. Turek F.W. Takahashi J.S. Science. 1994; 264: 719-725Crossref PubMed Scopus (1311) Google Scholar, 17Rutila J.E. Suri V. Le M. So W.V. Rosbash M. Hall J.C. Cell. 1998; 93: 805-814Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar, 18Kyriacou C.P. Hall J.C. Proc. Natl. Acad. Sci. U. S. A. 1980; 77: 6729-6733Crossref PubMed Scopus (277) Google Scholar, 19Konopka R.J. Benzer S. Proc. Natl. Acad. Sci. U. S. A. 1971; 68: 2112-2116Crossref PubMed Scopus (1622) Google Scholar, 20Sehgal A. Price J.L. Man B. Young M.W. Science. 1994; 263: 1603-1606Crossref PubMed Scopus (463) Google Scholar, 21Allada R. White N.E. So W.V. Hall J.C. Rosbash M. Cell. 1998; 93: 791-804Abstract Full Text Full Text PDF PubMed Scopus (574) Google Scholar), suggesting that this transcriptional loop is essential for normal clock function. Given these results, it is likely that the E-box enhancer element regulates the rhythmic expression of other genes within the SCN. However, the transcriptional activation of several circadian-regulated genes (vasopressin, brain-derived neurotrophic factor, Fos; Refs.22Kalsbeek A. Buijs R. Engelmann M. Wotjak C. Landgraf R. Brain Res. 1995; 682: 75-82Crossref PubMed Scopus (107) Google Scholar, 23Prosser R.A. Macdonald E.S. Heller H.C. Mol. Brain Res. 1994; 25: 151-156Crossref PubMed Scopus (43) Google Scholar, 24Liang F.Q. Walline R. Earnest D.J. Neurosci. Lett. 1998; 242: 89-92Crossref PubMed Scopus (93) Google Scholar) requires complex interactions of several different classes of enhancer elements (25Robertson L.M. Kerppola T.K. Vendrell M. Luk D. Smeyne R.J. Bocchiaro C. Morgan J.I. Curran T. Neuron. 1995; 14: 241-252Abstract Full Text PDF PubMed Scopus (270) Google Scholar, 26Tao X. Finkbeiner S. Arnold D.B. Shaywitz A.J. Greenberg M.E. Neuron. 1998; 20: 709-726Abstract Full Text Full Text PDF PubMed Scopus (1277) Google Scholar, 27Iwasaki Y. Oiso Y. Saito H. Majzoub J.A. Endocrinology. 1997; 138: 5266-5274Crossref PubMed Scopus (102) Google Scholar), suggesting the involvement of different transcription pathways in circadian gene regulation within the SCN. The elucidation of these pathways will provide valuable insight into the series of coordinated transcriptional events underlying circadian rhythmicity.Ostensibly, transcriptional pathways that contribute to SCN rhythmicity should have the capacity to integrate signaling information from a variety of stimuli, as well as possess properties that allow for its stringent regulation. One candidate is the CREB/CRE transcriptional pathway. This pathway has been shown to be activated by multiple kinases, including protein kinase A (PKA), Ca2+/calmodulin-dependent kinase, and mitogen-activated protein kinase (MAPK) (28Xing J. Ginty D.D. Greenberg M.E. Science. 1996; 273: 959-996Crossref PubMed Scopus (1081) Google Scholar, 29Gonzalez G.A. Montminy M.R. Cell. 1989; 59: 675-680Abstract Full Text PDF PubMed Scopus (2041) Google Scholar, 30Sheng M. Thompson M.A. Greenberg M.E. Science. 1991; 252: 1427-1430Crossref PubMed Scopus (1274) Google Scholar, 31Impey S. Obrietan K. Wong S.T. Poser S. Yano S. Wayman G. Deloulme J.C. Chan G. Storm D.R. Neuron. 1998; 21: 869-883Abstract Full Text Full Text PDF PubMed Scopus (764) Google Scholar). The CREB/CRE transcriptional pathway also has the capacity to integrate the activation of multiple signaling pathways and the strength of signal into striking variations in downstream gene transcription (32Bito H. Deisseroth K. Tsien R.W. Cell. 1996; 87: 1203-1214Abstract Full Text Full Text PDF PubMed Scopus (974) Google Scholar, 33Impey S. Mark M. Villacres E.C. Poser S. Chavkin C. Storm D.R. Neuron. 1996; 16: 973-982Abstract Full Text Full Text PDF PubMed Scopus (504) Google Scholar, 34Sheng M. McFadden G. Greenberg M.E. Neuron. 1990; 4: 571-782Abstract Full Text PDF PubMed Scopus (873) Google Scholar, 35Tan Y. Low K.G. Boccia C. Grossman J. Comb M.J. Mol. Cell. Biol. 1994; 14: 7546-7556Crossref PubMed Scopus (40) Google Scholar). Furthermore, CRE-mediated transcription can be rapidly repressed through a myriad of mechanisms, including inducible early cAMP repressor induction, phosphatase activation, or as a result of CREB heterodimerization with inhibitory transcription factors (32Bito H. Deisseroth K. Tsien R.W. Cell. 1996; 87: 1203-1214Abstract Full Text Full Text PDF PubMed Scopus (974) Google Scholar, 36Foulkes N.S. Sassone-Corsi P. Biophys. Acta. 1996; 1288: F101-F121PubMed Google Scholar). These unique functional properties led us to explore whether this transcriptional pathway plays a role in circadian rhythmicity. Toward this end, we used a mouse CRE-β-galactosidase transgenic reporter strain to monitor CRE-mediated transcription in vivo.DISCUSSIONThe results presented here show that the SCN exhibit a prominent circadian oscillation in CRE-mediated gene expression in dark-adapted animals. Furthermore, photic stimulation during the subjective night triggered CRE-dependent transcription, whereas light treatment during the subjective day was not effective. Transient transfection experiment revealed that the ERK/MAPK pathway activity is essential for Ca2+-dependent stimulation of CRE-mediated transcription in SCN cells. Together, these results provide the first evidence linking the CREB/CRE transcriptional pathway to endogenous timing mechanisms.Photic Stimulation of CRE-mediated TranscriptionThere is a large body of evidence suggesting that the phase-shifting effects of light result from new protein synthesis. However, the enhancer elements mediating transcriptional activation have not been thoroughly characterized. Our data suggest that the CRE may play a central role in the ability of light to activate gene expression and, in turn, phase-shift the clock. In support of this, we show that light induces CRE-mediated gene expression. Additionally, the finding that a brief 5-min light treatment triggers a highly localized induction of CRE-mediated gene expression correlates with a duration of light shown to phase-shift overt activity rhythms (11Kornhauser J.M. Nelson D.E. Mayo K.E. Takahashi J.S. Neuron. 1990; 5: 127-134Abstract Full Text PDF PubMed Scopus (455) Google Scholar). The general pattern of CRE-mediated gene expression, both temporally and anatomically, parallels the induction of several immediate early genes thought to be involved in phase-shifting the clock (11Kornhauser J.M. Nelson D.E. Mayo K.E. Takahashi J.S. Neuron. 1990; 5: 127-134Abstract Full Text PDF PubMed Scopus (455) Google Scholar, 12Kornhauser J.M. Nelson D.E. Mayo K.E. Takahashi J.S. Science. 1992; 255: 1581-1584Crossref PubMed Scopus (196) Google Scholar, 13Rusak B. Robertson H.A. Wisden W. Hunt S.P. Science. 1990; 248: 1237-1240Crossref PubMed Scopus (478) Google Scholar). Given that the promoters for these immediate early genes (including c-fos,junB, and NGFI-B) contain at least one CRE (48Amato S.F. Nakajima K. Hirano T. Chiles T.C. J. Immunol. 1996; 157: 146-155PubMed Google Scholar, 49Nakajima K. Kusafuka T. Takeda T. Fujitani Y. Nakae K. Hirano T. Mol. Cell. Biol. 1993; 13: 3027-3041Crossref PubMed Scopus (114) Google Scholar, 50Sassone-Corsi P. Visvader J. Ferland L. Mellon P.L. Verm I.M. Genes Dev. 1988; 2: 1529-1538Crossref PubMed Scopus (299) Google Scholar), it is reasonable to hypothesize that the CRE may play a central role in mediating the ability of light to trigger immediate early gene induction. Our results showing that light-induces CRE-regulated gene expression in a phase-restricted manner are consistent with work showing that light-induced CREB phosphorylation is restricted to the subjective night (40Ginty D.D. Kornhauser J.M. Thompson M.A. Bading H. Mayo K.E. Takahashi J.S. Greenberg M.E. Science. 1993; 260: 238-241Crossref PubMed Scopus (738) Google Scholar). These results suggest that stringent regulation of the CREB/CRE-transcriptional pathway during the day may be a critical element that confers the phase-restricted phase-shifting effects of light.Signaling PathwaysA role for Ca2+ in photic entrainment of the clock has been suggested by the finding that light-induced phase-shifts require NMDA receptor activation (8Colwell C.S. Foster R.G. Menaker M. Brain Res. 1991; 554: 105-110Crossref PubMed Scopus (117) Google Scholar). Given the evidence identifying a transcriptional component to light-induced phase shifts, we assessed the signaling mechanisms that couple Ca2+ to gene expression in the SCN. In primary cultures of SCN neurons, we found that increasing cytosolic Ca2+, either through high K+ or NMDA administration, resulted in enhanced CRE-dependent transcription. In addition, the co-activation of Ca2+ and cAMP pathways resulted in a robust synergistic activation of CRE-dependent transcription. Interestingly, besides glutamate, RHT nerve terminals also express PACAP (51Hannibal J. Ding J.M. Chen D. Fahrenkrug J. Larsen P.J. Gillette M.U. Mikkelsen J.D. J. Neurosci. 1997; 17: 2637-2644Crossref PubMed Google Scholar), a peptide capable of stimulating cAMP production. Light-induced release of transmitters capable of stimulating Ca2+ and cAMP pathways may be important for robust activation of the CREB/CRE transcriptional pathway in the SCN. Along these lines, we have observed that modest stimulation of cAMP signaling pathways that, alone, was unable to increase CRE-mediated transcription, potently augmented Ca2+-dependent CRE-mediated transcription in the SCN. 2K. Obrietan and D. R. Storm, unpublished observation. CRE-mediated gene expression is regulated by a variety of cellular stimuli acting through a number of different kinase cascades (28Xing J. Ginty D.D. Greenberg M.E. Science. 1996; 273: 959-996Crossref PubMed Scopus (1081) Google Scholar, 29Gonzalez G.A. Montminy M.R. Cell. 1989; 59: 675-680Abstract Full Text PDF PubMed Scopus (2041) Google Scholar, 30Sheng M. Thompson M.A. Greenberg M.E. Science. 1991; 252: 1427-1430Crossref PubMed Scopus (1274) Google Scholar, 31Impey S. Obrietan K. Wong S.T. Poser S. Yano S. Wayman G. Deloulme J.C. Chan G. Storm D.R. Neuron. 1998; 21: 869-883Abstract Full Text Full Text PDF PubMed Scopus (764) Google Scholar). Our work shows that Ca2+ stimulation of CRE-mediated transcription was dependent upon activation of the MAPK signaling pathway. Cotransfection with a dominant-negative interfering form of MEK or treatment with the MEK inhibitor PD 98059 blocked Ca2+-stimulated gene expression. Coupling of Ca2+ to activation of the MAPK cascade has been shown to be dependent upon an enhancement of Ras-GTPase catalytic activity (52Rosen L.B. Ginty D.D. Weber M. Greenberg M.E. Neuron. 1994; 12: 1207-1221Abstract Full Text PDF PubMed Scopus (595) Google Scholar). Ca2+-dependent Ras activation is triggered by a variety of signaling intermediates, including calmodulin kinases (42Enslen H. Sun P. Brickey D. Soderling S.H. Klamo E. Soderling T.R. J. Biol. Chem. 1994; 269: 15520-15527Abstract Full Text PDF PubMed Google Scholar,53Chen H.J. Rojas-Soto M. Oguni A. Kennedy M.B. Neuron. 1998; 20: 895-904Abstract Full Text Full Text PDF PubMed Scopus (479) Google Scholar), Src (54Rusanescu G. Qi H. Thomas S.M. Brugge J.S. Halegoua S. Neuron. 1995; 15: 1415-1425Abstract Full Text PDF PubMed Scopus (233) Google Scholar), Ras-GRF (55Farnsworth C.L. Freshney N.W. Rosen L.B. Ghosh A. Greenberg M.E. Feig L.A. Nature. 1995; 376: 524-527Crossref PubMed Scopus (390) Google Scholar), and the epidermal growth factor receptor (56Rosen L.B. Greenberg M.E. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 1113-1118Crossref PubMed Scopus (172) Google Scholar). The MAPK pathway gains access to the nucleus via the activation-dependent nuclear translocation of ERK. ERK has been shown to triggered CREB phosphorylation through activation of RSK 1, 2, and 3, all of which are CREB kinases (57Xing J. Kornhauser J.M. Xia Z. Thiele E.A. Greenberg M.E. Mol. Cell. Biol. 1998; 18: 1946-1955Crossref PubMed Google Scholar). A requirement for MAPK activity was also revealed by the observation that Ca2+-induced CREB phosphorylation was attenuated by the MEK inhibitor PD 98059. In addition, forskolin-stimulated CREB phosphorylation was reduced by PD 98059, indicating that the cAMP-dependent signaling pathway acts, in part, via activation of the MAPK cascade. Along these lines, cAMP has been shown to activate the MAPK cascade in hippocampal and cortical neurons (31Impey S. Obrietan K. Wong S.T. Poser S. Yano S. Wayman G. Deloulme J.C. Chan G. Storm D.R. Neuron. 1998; 21: 869-883Abstract Full Text Full Text PDF PubMed Scopus (764) Google Scholar).Within the SCN, elevated cytosolic Ca2+ has been shown to trigger CREB phosphorylation through a mechanism requiring the production of nitric oxide (58Ding J.M. Faiman L.E. Hurst W.J. Kuriashkina L.R. Gillette M.U. J. Neurosci. 1997; 17: 667-675Crossref PubMed Google Scholar). Recently, Ca2+-dependent nitric oxide activation was shown to elicit ERK phosphorylation in neuronal cultures (59Yun H.Y. Gonzalez-Zulueta M. Dawson V.L. Dawson T.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5773-5778Crossref PubMed Scopus (176) Google Scholar), thus providing a pathway by which light-induced nitric oxide production could trigger sequential MAPK activation. Although other transcription factors may be activated by increased cytosolic Ca2+, it is intriguing to note that nitric oxide synthetase antagonism blocks both glutamate-induced CREB-phosphorylation and glutamate-induced phase-shifts (58Ding J.M. Faiman L.E. Hurst W.J. Kuriashkina L.R. Gillette M.U. J. Neurosci. 1997; 17: 667-675Crossref PubMed Google Scholar, 60Ding J.M. Chen D. Weber E.T. Faiman L.E. Rea M.A. Gillette M.U. Science. 1994; 266: 1713-1717Crossref PubMed Scopus (500) Google Scholar). This suggests a strong correlation between clock phase-shifting and the activation of a transcriptional pathway involved in triggering CRE-mediated gene expression. Taken together, the results presented here provide a mechanism by which glutamate receptor stimulation leads to CRE-dependent transcription.Endogenous RhythmicityRhythmic transcription appears to be central to maintaining circadian timekeeping. For example, a mutated form of the putative transcription factor CLOCK abolishes circadian activity rhythms under D/D conditions (16Vitaterna M.H. King D.P. Chang A.M. Kornhauser J.M. Lowrey P.L. McDonald J.D. Dove W.F. Pinto L.H. Turek F.W. Takahashi J.S. Science. 1994; 264: 719-725Crossref PubMed Scopus (1311) Google Scholar). Our data show that CRE-mediated gene expression is regulated in a circadian manner under free-running conditions. Levels of reporter protein began to rise during the late subjective night and peaked during mid-subjective day. Given the approximately 6 h between transcription and maximal reporter expression, one may deduce that induction of CRE-mediated gene expression is restricted to the subjective night, and possibly the early subjective morning. This result indicates that the phase-dependent regulation of endogenous CRE-mediated gene rhythmicity overlaps with the phase dependence of light inducible CRE-mediated gene expression, suggesting that a similar signaling mechanism may govern both processes.It is unclear why the light-evoked stimulation of CRE-mediated gene expression was greater than the peak in reporter expression resulting from endogenous pacemaker activity. Possible explanations may include more robust activation of signaling pathways by light or synergism between signaling pathways that are activated by light and the endogenous clock. Interestingly, we recently reported that light triggers MAPK activation in the SCN, and that MAPK activity is regulated in a circadian manner in the SCN under D/D conditions (61Obrietan K. Impey S. Storm D.R. Nat. Neurosci. 1998; 1: 693-700Crossref PubMed Scopus (316) Google Scholar).Recent work performed in Drosophila has revealed a robust circadian oscillation in CRE-mediated gene expression and an interdependence between rhythmic CRE-dependent transcription and period oscillations, indicating that the CRE transcriptional pathway is a component of the circadian clock (74Belvin M.P. Zhou H. Yin J.C.P. Neuron. 1999; 22: 777-787Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). Further work in mammalian systems may reveal a similar interaction between the CRE transcriptional pathway and period homolog rhythmicity.Circadian variations in the phosphorylation state of the transcription factor CREB at Ser-133 were also observed. The peak in the P-CREB rhythm preceded the reporter gene peak by approximately 6 h, an expected time lag for transcriptional activation and maximal protein expression. The circadian P-CREB rhythm does not result from CREB oscillations, since levels of CREB in the SCN were stable at subjective day versus night time points. This result suggests that circadian oscillations in P-CREB result from circadian fluctuations in the activation state of CREB kinases or phosphatases.It is unclear how rhythmic CRE-mediated gene expression is maintained under free-running conditions. However there are several plausible explanations. Given that extracellular membrane receptor-mediated signaling events regulate CRE-mediated gene expression, one may expect to observe circadian changes in the level of extracellular transmitters capable of eliciting CRE-mediated gene expression. In support of this idea, circadian variations in the concentrations of excitatory amino acids have been observed within the region of the SCN under free-running conditions, and in slice preparations (62Glass J.D. Hauser U.E. Blank J.L. Selim M. Rea M.A. Am. J. Physiol. 1993; 265: R504-R511PubMed Google Scholar, 63Honma S. Katsuno Y. Shinohara K. Abe H. Honma K. Am. J. Physiol. 1996; 271: R579-R585Crossref PubMed Google Scholar, 64Shinohara K. Honma S. Katsuno Y. Abe H. Honma K. Neuroreport. 1998; 9: 137-140Crossref PubMed Scopus (32) Google Scholar). Circadian oscillations in CRE-dependent transcription also may be a result of an inherent rhythmic transcriptional program of SCN pacemaker cells. Another possibility is that the amount or ratio of CREB heterodimerization partners within the SCN varies over the circadian cycle. In support of this idea, CREM-deficient mice do not express circadian locomotor activity. 3P. Sassone Corsi, personal communication. The circadian expression of a variety of genes within the SCN may result from circadian CRE-dependent transcription. For example, the promoters for several peptides that show circadian oscillations at the mRNA or protein level in the SCN, including vasopressin, somatostatin, and, during development, vasoactive intestinal peptide (22Kalsbeek A. Buijs R. Engelmann M. Wotjak C. Landgraf R. Brain Res. 1995; 682: 75-82Crossref PubMed Scopus (107) Google Scholar, 65Ban Y. Shigeyoshi Y. Okamura H. J. Neurosci. 1997; 17: 3920-3931Crossref PubMed Google Scholar, 66Yang J. Tominaga K. Otori Y. Fukuhara C. Tokumasu A. Inouye S. Mol. Cell. Neurosci. 1994; 5: 97-102Crossref PubMed Scopus (10) Google Scholar), contain one or more CREs (67- 69). Interestingly, these peptides have the capacity to both modulate CRE-dependent transcription, either positively or negatively (70Deutsch P.J. Sun Y. Kroog G.S. J. Biol. Chem. 1990; 265: 10274-10281Abstract Full Text PDF PubMed Google Scholar, 71Tentler J.J. Hadcock J.R. Gutierrez-Hartmann A. Mol. Endocrin. 1997; 11: 859-866Crossref PubMed Scopus (45) Google Scholar, 72Yasui M. Zelenin S.M. Celsi G. Aperia A. Am. J. Physiol. 1997; 272: F443-F450PubMed Google Scholar), and to alter rhythmicity when added to the SCN (47Piggins H.D. Antle M.C. Rusak B. J. Neurosci. 1995; 15: 5612-5622Crossref PubMed Google Scholar, 73Hamada T. Shibata S. Tsuneyoshi A. Tominaga K. Watanabe S. Am. J. Physiol. 1993; 265: PR1199-PR1204Google Scholar). Conceivably, the circadian expression of these proteins could be generated by temporally overlapping feedback loops that either activate or inhibit CRE-mediated transcription. Based on the results presented here, we propose that the CRE transcriptional pathway plays an important role in orchestrating the series of transcriptional events essential for both endogenous clock rhythmicity and the ability of light to phase-shift the clock. In mammals, the suprachiasmatic nuclei (SCN) 1The abbreviations used are: SCN, suprachiasmatic nuclei; CRE, cAMP response element; CREB, CRE-binding protein; P-CREB, phospho-active CREB; MAPK, mitogen-activated protein kinase; PKA, protein kinase A; L, light; D, dark; CT, circadian time; PBS, phosphate-buffered saline; PBST, PBS with Triton X-100; RHT, retinohypothalamic tract; ERK, extracellular signal-regulated kinase; D/N, dominant negative; DM, dissociation medium; MEK, MAPK kinase. 1The abbreviations used are: SCN, suprachiasmatic nuclei; CRE, cAMP response element; CREB, CRE-binding protein; P-CREB, phospho-active CREB; MAPK, mitogen-activated protein kinase; PKA, protein kinase A; L, light; D, dark; CT, circadian time; PBS, phosphate-buffered saline; PBST, PBS with Triton X-100; RHT, retinohypothalamic tract; ERK, extracellular signal-regulated kinase; D/N, dominant negative; DM, dissociation medium; MEK, MAPK kinase. of the hypothalamus contain a circadian oscillator that functions as the major biological clock (1Hastings M.H. Best J.D. Ebling F.J. Maywood E.S. McNulty S. Schurov I. Selvage D. Sloper P. Smith K.L. Brain Res. 1996; 111: 147-174Crossref Google Scholar, 2Miller J.D. Morin L.P. Schwartz W.J. Moore R.Y. Sleep. 1996; 19: 641-667Crossref PubMed Scopus (155) Google Scholar, 3van den Pol A.N. Dudek F.E. Neurosci. 1993; 56: 793-811Crossref PubMed Scopus (149) Google Scholar). The biorhythm generated by the SCN allows an organism to predict and coordinate its daily physiological processes to an approximate 24-h period. If the SCN are lesioned, there is a loss of physiological and behavioral circadian rhythms (4Moore R.Y. Eichler V.B. Brain Res. 1972; 42: 201-206Crossref PubMed Scopus (1604) Google Scholar, 5Stephan F.K. Zucker I. Proc. Natl. Acad. Sci. U. S. A. 1972; 69: 1583-1586Crossref PubMed Scopus (1547) Google Scholar). The most effective regulator of the endogenous clock is light; endogenous clock rhythmicity is entrained to the environmental light cycle by photic cues conveyed from the eyes to the SCN via the retinohypothalamic tract (RHT) (6Moore R.Y. Lenn N.J. J. Comp. Neurol. 1972; 146: 1-14Crossref PubMed Scopus (1015) Google Scholar). For example, if an animal receives a light flash during the dark phase of the day/night light cycle, the circadian rhythm is reset, or phase-shifted (7Daan S. Pittendrigh C.S. J. Comp. Physiol. 1976; 106: 253-266Crossref Scopus (254) Google Scholar). Light-indu" @default.
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• W2032656475 title "Circadian Regulation of cAMP Response Element-mediated Gene Expression in the Suprachiasmatic Nuclei" @default.
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