Abstract
Clock genes Cry1 and Cry2, inhibitory components of core molecular feedback loop, are regarded as critical molecules for the circadian rhythm generation in mammals. A double knockout of Cry1 and Cry2 abolishes the circadian behavioral rhythm in adult mice under constant darkness. However, robust circadian rhythms in PER2::LUC expression are detected in the cultured suprachiasmatic nucleus (SCN) of Cry1/Cry2 deficient neonatal mice and restored in adult SCN by co-culture with wild-type neonatal SCN. These findings led us to postulate the compensatory molecule(s) for Cry1/Cry2 deficiency in circadian rhythm generation. We examined the roles of Chrono and Dec1/Dec2 proteins, the suppressors of Per(s) transcription similar to CRY(s). Unexpectedly, knockout of Chrono or Dec1/Dec2 in the Cry1/Cry2 deficient mice did not abolish but decoupled the coherent circadian rhythm into three different periodicities or significantly shortened the circadian period in neonatal SCN. DNA microarray analysis for the SCN of Cry1/Cry2 deficient mice revealed substantial increases in Per(s), Chrono and Dec(s) expression, indicating disinhibition of the transactivation by BMAL1/CLOCK. Here, we conclude that Chrono and Dec1/Dec2 do not compensate for absence of CRY1/CRY2 in the circadian rhythm generation but contribute to the coherent circadian rhythm expression in the neonatal mouse SCN most likely through integration of cellular circadian rhythms.
Highlights
Clock genes Cry[1] and Cry[2], inhibitory components of core molecular feedback loop, are regarded as critical molecules for the circadian rhythm generation in mammals
We found that Chrono and Dec1/Dec[2] expression were substantially increased in the suprachiasmatic nucleus (SCN) of Cry1/Cry[2] deficient mice, indicating disinhibition of the transactivation by BMAL1/CLOCK
DNA microarray analysis revealed that the expression ratio (Cry1/Cry[2] deficient vs control) increased significantly in Dec[1], Dec[2] and Chrono in addition to Per[1] and Per[2] in the neonatal SCN (Fig. 1)
Summary
Clock genes Cry[1] and Cry[2], inhibitory components of core molecular feedback loop, are regarded as critical molecules for the circadian rhythm generation in mammals. The circadian rhythm in mammals is regarded as generated by the core molecular auto-feedback loop involving the clock genes, Period (Per[1], Per2), Cryptochrome (Cry[1], Cry2), Bmal[1], and Clock, and their protein p roducts[1] In this loop, the heterodimer of BMAL1/CLOCK binds to E-box enhancer elements located on the Per1/Per[2] or Cry1/Cry[2] promoter and activates transcription of Per(s) and Cry(s). DEC1 and DEC2 are basic helix–loop–helix transcription factors, which have been suggested as additional negative components of the core molecular loop[6] They are able to bind to the E-box cis-elements and repress CLOCK/BMAL1-mediated transactivation of Per[1] and Per[2]. We proposed that CHRONO and DEC1/DEC2 are candidate molecules for the compensation of CRY1/CRY2 function in the core molecular loop[11]
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