Program in Molecular Medicine
Amino Acids, Peptides, and Proteins | Developmental Biology | Molecular Biology | Molecular Genetics | Nucleic Acids, Nucleotides, and Nucleosides
MicroRNAs target complementary mRNAs for degradation or translational repression, reducing or preventing protein synthesis. In Caenorhabditis elegans, the transcription factor HBL-1 (Hunchback-like 1) promotes early larval (L2)-stage cell fates, and the let-7 family microRNAs temporally downregulate HBL-1 to enable the L2-to-L3 cell-fate progression. In parallel to let-7-family microRNAs, the conserved RNA-binding protein LIN-28 and its downstream gene lin-46 also act upstream of HBL-1 in regulating the L2-to-L3 cell-fate progression. The molecular function of LIN-46, and how the lin-28-lin-46 pathway regulates HBL-1, are not understood. Here, we report that the regulation of HBL-1 by the lin-28-lin-46 pathway is independent of the let-7/lin-4 microRNA complementary sites (LCSs) in the hbl-1 3'UTR, and involves stage-specific post-translational regulation of HBL-1 nuclear accumulation. We find that LIN-46 is necessary and sufficient to prevent nuclear accumulation of HBL-1. Our results illuminate that robust progression from L2 to L3 cell fates depends on the combination of two distinct modes of HBL-1 downregulation: decreased synthesis of HBL-1 via let-7-family microRNA activity, and decreased nuclear accumulation of HBL-1 via action of the lin-28-lin-46 pathway.
Cell-fate progression, Developmental robustness, Heterochronic, Nuclear-cytoplasmic partitioning, Transcription factor, microRNA
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© 2019. Published by The Company of Biologists Ltd, http://www.biologists.com/user-licence-1-1/. Publisher PDF posted as allowed by the publisher's self-archiving policy at https://dev.biologists.org/content/rights-permissions.
DOI of Published Version
Ilbay O, Ambros V. Regulation of nuclear-cytoplasmic partitioning by the lin-28-lin-46 pathway reinforces microRNA repression of HBL-1 to confer robust cell-fate progression in C. elegans. Development. 2019 Nov 6;146(21):dev183111. doi: 10.1242/dev.183111. PMID: 31597658; PMCID: PMC6857590. Link to article on publisher's site
Development (Cambridge, England)
Ilbay O, Ambros VR. (2019). Regulation of nuclear-cytoplasmic partitioning by the lin-28-lin-46 pathway reinforces microRNA repression of HBL-1 to confer robust cell-fate progression in C. elegans. Program in Molecular Medicine Publications. https://doi.org/10.1242/dev.183111. Retrieved from https://escholarship.umassmed.edu/pmm_pp/141