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 funda mental component of the circadian clock Although recent work has implicated a role for E-box-dependent transcription in circadian rhythmicity, the con tribution of other enhancer elements has yet to be assessed. Here, we repor t that cells of the supra-chiasmatic nuclei (SCN) exhibit a prominent circa dian oscillation in cAMP response dement (CRE)-mediated gene expression. Ma ximal reporter gene expression occurred from late-subjective night to mid-s ubjective day. Cycling of CRE-dependent transcription was not observed in o ther brain regions, including the supraoptic nucleus and piriform cortex. L evels of the phospho-active form of the transcription factor CREB (P-CBEB) varied as a function of circadian time, peak P-CREB levels occurred during the mid- to late-subjective night. Furthermore, photic stimulation during t he subjective might, but not during the subjective day, triggered a marked increase in CRE-mediated gene expression in the SCN. Reporter gene experime nts showed that activation of the p44/42 mitogen-activated protein kinase s ignaling cascade is required for Ca2+-dependent stimulation of CRE-mediated transcription in the SCN. These findings reveal the CREB/CRE transcription al pathway to be circadian-regulated within the SCN, and raise the possibil ity that this pathway provides signaling information essential for normal c lock function.