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Feedback between a retinoid-related nuclear receptor and the let-7 microRNAs controls the pace and number of molting cycles in C. elegans

Ruhi Patel, Himani Galagali, John K. Kim, Alison R. Frand
doi: https://doi.org/10.1101/506261
Ruhi Patel
1Department of Biological Chemistry, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA 90095
3Department of Molecular Immunology and Microbiology, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA 90095
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Himani Galagali
2Department of Biology, Johns Hopkins University Baltimore, MD 21218
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John K. Kim
2Department of Biology, Johns Hopkins University Baltimore, MD 21218
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  • For correspondence: jnkim@jhu.edu afrand@mednet.ucla.edu
Alison R. Frand
1Department of Biological Chemistry, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, CA 90095
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  • For correspondence: jnkim@jhu.edu afrand@mednet.ucla.edu
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SUMMARY

Animal development requires coordination among cyclic processes, sequential cell fate specifications, and once-a-lifetime morphogenic events, but the underlying mechanisms are not well understood. C. elegans undergo four molts at regular 8–10 h intervals. The pace of the cycle is governed by PERIOD/lin-42 and other as-yet unknown factors. Cessation of the cycle in young adults is controlled by the let-7 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 retinoid-related orphan receptors (RORs), and the let-7 family of microRNAs that regulates both the frequency and finite number of molts. The molting cycle is decelerated in nhr-23 knockdowns, accelerated in let-7(-) mutants, and similar to wild type animals in let-7(-) nhr-23(-) double mutants. NHR-23 binds response elements (ROREs) in the let-7 promoter and activates transcription. In turn, let-7 dampens nhr-23 expression across development via a complementary let-7 binding site (LCS) in the nhr-23 3′ UTR. The molecular interactions between NHR-23 and let-7 hold true for other let-7 family microRNAs. 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. NHR-23 and let-7 also co-regulate scores of genes required for execution of the molts, including lin-42. In addition, ROREs and LCSs isolated from mammalian ROR and let-7 genes function in C. elegans, 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.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 06, 2022.
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Feedback between a retinoid-related nuclear receptor and the let-7 microRNAs controls the pace and number of molting cycles in C. elegans
Ruhi Patel, Himani Galagali, John K. Kim, Alison R. Frand
bioRxiv 506261; doi: https://doi.org/10.1101/506261
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Feedback between a retinoid-related nuclear receptor and the let-7 microRNAs controls the pace and number of molting cycles in C. elegans
Ruhi Patel, Himani Galagali, John K. Kim, Alison R. Frand
bioRxiv 506261; doi: https://doi.org/10.1101/506261

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