Timekeeping is a critical component of animal development. We propose that this feedback loop unites the molting timer and the heterochronic gene regulatory network, possibly by functioning as a cycle counter. elegans, suggesting conservation of this feedback mechanism. In addition, ROREs and LCSs isolated from mammalian ROR and let-7 genes function in C. NHR-23 and let-7 also coregulate scores of genes required for execution of the molts, including lin-42. Either derepression of nhr-23 transcripts by LCS deletion or high gene dosage of nhr-23 leads to protracted behavioral quiescence and extra molts in adults. The molecular interactions between NHR-23 and let-7 hold true for other let-7 family microRNAs. In turn, let-7 dampens nhr-23 expression across development via a complementary let-7-binding site (LCS) in the nhr-23 3′ UTR. NHR-23 binds response elements (ROREs) in the let-7 promoter and activates transcription. The molting cycle is decelerated in nhr-23 knockdowns and accelerated in let-7(−) mutants, but timed similarly in let-7(−) nhr-23(−) double mutants and wild-type animals. Here, we characterize a negative feedback loop between NHR-23, the worm homolog of mammalian retinoid-related orphan receptors (RORs), and the let-7 family of microRNAs that regulates both the frequency and finite number of molts. Cessation of the cycle in young adults is controlled by the let-7 family of microRNAs and downstream transcription factors in the heterochronic pathway. The pace of the cycle is governed by PERIOD/ lin-42 and other as-yet unknown factors. Caenorhabditis elegans undergoes four molts at regular 8 to 10 hour intervals. 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.
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