Feedback between a retinoid-related nuclear receptor and the microRNAs controls the pace and number of molting cycles in .

Animal development requires coordination among cyclic processes, sequential cell fate specifications, and once-a-lifetime morphogenic events, but the underlying timing mechanisms are not well understood. undergoes four molts at regular 8 to 10 hour intervals. The pace of the cycle is governed by PERIOD/ and other as-yet unknown factors. Cessation of the cycle in young adults is controlled by the family of microRNAs and downstream transcription factors in the heterochronic pathway. Here, we characterize a negative feedback loop between NHR-23, the worm homolog of mammalian etinoid-related rphan eceptors (RORs), and the family of microRNAs that regulates both the frequency and finite number of molts. The molting cycle is decelerated in knockdowns and accelerated in mutants, but timed similarly in double mutants and wild-type animals. NHR-23 binds response elements (ROREs) in the promoter and activates transcription. In turn, 7 dampens expression across development via a complementary -binding site (LCS) in the 3' UTR. The molecular interactions between NHR-23 and hold true for other family microRNAs. Either derepression of transcripts by LCS deletion or high gene dosage of leads to protracted behavioral quiescence and extra molts in adults. NHR-23 and also coregulate scores of genes required for execution of the molts, including . In addition, ROREs and LCSs isolated from mammalian and genes function in , suggesting conservation of this feedback mechanism. We propose that this feedback loop unites the molting timer and the heterochronic gene regulatory network, possibly by functioning as a cycle counter.