A feedback circuit involving let-7-family miRNAs and DAF-12 integrates environmental signals and developmental timing in Caenorhabditis elegans

Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18668-73. doi: 10.1073/pnas.0908131106. Epub 2009 Oct 14.

Abstract

Animal development is remarkably robust; cell fates are specified with spatial and temporal precision despite physiological and environmental contingencies. Favorable conditions cause Caenorhabditis elegans to develop rapidly through four larval stages (L1-L4) to the reproductive adult. In unfavorable conditions, L2 larvae can enter the developmentally quiescent, stress-resistant dauer larva stage, enabling them to survive for prolonged periods before completing development. A specific progression of cell division and differentiation events occurs with fidelity during the larval stages, regardless of whether an animal undergoes continuous or dauer-interrupted development. The temporal patterning of developmental events is controlled by the heterochronic genes, whose products include microRNAs (miRNAs) and regulatory proteins. One of these proteins, the DAF-12 nuclear hormone receptor, modulates the transcription of certain let-7-family miRNAs, and also mediates the choice between the continuous vs. dauer-interrupted life history. Here, we report a complex feedback loop between DAF-12 and the let-7-family miRNAs involving both the repression of DAF-12 by let-7-family miRNAs and the ligand-modulated transcriptional activation and repression of the let-7-Fam miRNAs by DAF-12. We propose that this feedback loop functions to ensure robustness of cell fate decisions and to coordinate cell fate with developmental arrest.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Caenorhabditis elegans / growth & development*
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Environment*
  • Feedback, Physiological*
  • Gene Expression Regulation, Developmental
  • Ligands
  • MicroRNAs / metabolism*
  • Models, Biological
  • Mutation / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism*
  • Time Factors

Substances

  • Caenorhabditis elegans Proteins
  • DAF-12 protein, C elegans
  • Ligands
  • MicroRNAs
  • Receptors, Cytoplasmic and Nuclear
  • let-7 microRNA, C elegans