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.