Expression of Clock Gene Products in the Suprachiasmatic Nucleus in Relation to Circadian Behaviour

Summary

Circadian timing within the suprachiasmatic nucleus (SCN) is modelled around cell-autonomous, autoregulatory transcriptional/post-translational feedback loops, in which protein products of canonical clock genes Period and Cryptochrome periodically oppose transcription driven by CLOCK:BMAL complexes. Consistent with this model, mCLOCK is a nuclear antigen constitutively expressed in mouse SCN, whereas nuclear mPER and mCRY are expressed rhythmically. Peaking in late subjective day, mPER and mCRY form heteromeric complexes with mCLOCK, completing the negative feedback loop as levels of mPer and mCry mRNA decline. Circadian resetting by light or non-photic resetting (mediated by neuropeptide Y) involves acute up- and down-regulation of mPer mRNA, respectively. Expression of Per mRNA also peaks in subjective day in the SCN of the ground squirrel, indicating common clock and entrainment mechanisms for nocturnal and diurnal species. Oscillation within the SCN is dependent on intercellular signals, in so far as genetic ablation of the VPAC2 receptor for vasoactive intestinal polypeptide (VIP) suspends SCN circadian gene expression. The pervasive effect of the SCN on peripheral physiology is underscored by cDNA microarray analysis of the circadian gene expression in liver, which involves ca. 10% of the genome and almost all aspects of cell function. Moreover, the same molecular regulatory mechanisms driving the SCN appear also to underpin peripheral cycles.