CHRONO and DEC1/DEC2 compensate for lack of CRY1/CRY2 in expression of coherent circadian rhythm but not in generation of circadian oscillation in the neonatal mouse SCN

<jats:title>Abstract</jats:title><jats:p>Clock genes <jats:italic>Cry1</jats:italic> and <jats:italic>Cry2</jats:italic>, inhibitory components of core molecular feedback loop, are regarded as critical molecules for the circadian rhythm generation in mammals. A double knockout of <jats:italic>Cry1</jats:italic> and <jats:italic>Cry2</jats:italic> 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 <jats:italic>Cry1</jats:italic>/<jats:italic>Cry2</jats:italic> 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 <jats:italic>Cry1/Cry2</jats:italic> deficiency in circadian rhythm generation. We examined the roles of <jats:italic>Chrono</jats:italic> and <jats:italic>Dec1/Dec2</jats:italic> proteins, the suppressors of <jats:italic>Per(s)</jats:italic> transcription similar to CRY(s). Unexpectedly, knockout of <jats:italic>Chrono</jats:italic> or <jats:italic>Dec1</jats:italic>/<jats:italic>Dec2</jats:italic> in the <jats:italic>Cry1</jats:italic>/<jats:italic>Cry2</jats:italic> 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 <jats:italic>Cry1</jats:italic>/<jats:italic>Cry2</jats:italic> deficient mice revealed substantial increases in <jats:italic>Per</jats:italic>(s), <jats:italic>Chrono</jats:italic> and <jats:italic>Dec</jats:italic>(s) expression, indicating disinhibition of the transactivation by BMAL1/CLOCK. Here, we conclude that <jats:italic>Chrono</jats:italic> and <jats:italic>Dec1</jats:italic>/<jats:italic>Dec2</jats:italic> 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.</jats:p>