Clock and light regulation of the CREB coactivator CRTC1 in the suprachiasmatic circadian clock

Abstract

The CREB/CRE transcriptional pathway has been implicated in circadian clock timing and light-evokedclockresetting. Todate, muchof the work on CREB in circadian physiology has focused on how changes in the phosphorylation state of CREB regulate the timing processes. However, beyond changes in phosphorylation, CREB-dependent transcription can also be regulated by the CREB coactivator CRTC (CREB-regulated transcription coactivator), also known as TORC (transducer of regulated CREB). Here we profiled both the rhythmic and light-evoked regulation of CRTC1 and CRTC2 in the murine suprachiasmatic nucleus (SCN), the locus of the master mammalian clock. Immunohistochemical analysis revealed rhythmic expression of CRTC1 in the SCN. CRTC1 expression was detected throughout the dorsoventral extent of the SCN in the middle of the subjective day, with limited expression during early night, and late night expression levels intermediate between mid-day and early night levels. In contrast to CRTC1, robust expression of CRTC2 was detected during both the subjective day and night. During early and late subjective night, a brief light pulse induced strong nuclear accumulationofCRTC1intheSCN. IncontrastwithCRTC1, photicstimulationdidnotaffectthesubcellularlocalizationofCRTC2inthe SCN. Additionally, reportergeneprofilingandchromatinimmunoprecipitationanalysisindicatedthatCRTC1wasassociatedwithCREB in the 5 regulatory region of the period1 gene, and that overexpression of CRTC1 leads to a marked upregulation in period1 transcription. Together, these data raise the prospect that CRTC1 plays a role in fundamental aspects of SCN clock timing and entrainment. © 2013 the authors.