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FOXO transcription factors regulate development, longevity, and stress-resistance across species. The C. elegans FOXO ortholog, daf-16, has three major isoforms with distinct promoters and N-termini. Different combinations of isoforms regulate different processes. Adverse environments can induce dauer diapause after the second larval molt. During dauer, daf-16 blocks specification of vulval precursor cells, including EGFR/Ras-mediated 1˚ fate specification and LIN-12/Notch-mediated 2˚ fate specification. Using isoform-specific mutants, we find that daf-16a and daf-16f are functionally redundant for the block to the expression of 1˚ fate markers. In contrast, all three isoforms contribute to blocking the expression of 2˚ fate markers.
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daf-16/FOXO blocks adult cell fate in Caenorhabditis elegans dauer larvae via lin-41/TRIM71
Many tissue-specific stem cells maintain the ability to produce multiple cell types during long periods of non-division, or quiescence. FOXO transcription factors promote quiescence and stem cell maintenance, but the mechanisms by which FOXO proteins promote multipotency during quiescence are still emerging. The single FOXO ortholog in C . elegans , daf-16 , promotes entry into a quiescent and stress-resistant larval stage called dauer in response to adverse environmental cues. During dauer, stem and progenitor cells maintain or re-establish multipotency to allow normal development to resume after dauer. We find that during dauer, daf-16 /FOXO prevents epidermal stem cells (seam cells) from prematurely adopting differentiated, adult characteristics. In particular, dauer larvae that lack daf-16 misexpress collagens that are normally adult-enriched. Using col-19p :: gfp as an adult cell fate marker, we find that all major daf-16 isoforms contribute to opposing col-19p :: gfp expression during dauer. By contrast, daf-16(0) larvae that undergo non-dauer development do not misexpress col-19p :: gfp . Adult cell fate and the timing of col-19p :: gfp expression are regulated by the heterochronic gene network, including lin-41 and lin-29 . lin-41 encodes an RNA-binding protein orthologous to LIN41/TRIM71 in mammals, and lin-29 encodes a conserved zinc finger transcription factor. In non-dauer development, lin-41 opposes adult cell fate by inhibiting the translation of lin-29 , which directly activates col-19 transcription and promotes adult cell fate. We find that during dauer, lin-41 blocks col-19p :: gfp expression, but surprisingly, lin-29 is not required in this context. Additionally, daf-16 promotes the expression of lin-41 in dauer larvae. The col-19p :: gfp misexpression phenotype observed in dauer larvae with reduced daf-16 requires the downregulation of lin-41 , but does not require lin-29 . Taken together, this work demonstrates a novel role for daf-16 /FOXO as a heterochronic gene that promotes expression of lin-41/ TRIM71 to contribute to multipotent cell fate in a quiescent stem cell model.
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- Award ID(s):
- 1652283
- PAR ID:
- 10318312
- Editor(s):
- Murphy, Coleen T.
- Date Published:
- Journal Name:
- PLOS Genetics
- Volume:
- 17
- Issue:
- 11
- ISSN:
- 1553-7404
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1371/journal.pgen.1009881
