Circadian regulation of cAMP response element-mediated gene expression in the suprachiasmatic nuclei.
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.
Obrietan
K
K
Department of Pharmacology, University of Washington, Seattle, Washington 98195-7280, USA.
Impey
S
S
Smith
D
D
Athos
J
J
Storm
D R
DR
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002940:Circadian Rhythm; D000242:Cyclic AMP / Q000235:genetics* / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D004742:Enhancer Elements, Genetic; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007150:Immunohistochemistry; D008027:Light; D051379:Mice; D008822:Mice, Transgenic; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010750:Phosphoproteins / Q000235:genetics; D010766:Phosphorylation; D015398:Signal Transduction; D013493:Suprachiasmatic Nucleus / Q000378:metabolism*
D017362:Cyclic AMP Response Element-Binding Protein; D010750:Phosphoproteins; D000242:Cyclic AMP; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D002118:Calcium