A feedback circuit involving let-7-family miRNAs and DAF-12 integrates environmental signals and developmental timing in Caenorhabditis elegans.
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.
Hammell
Christopher M
CM
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Karp
Xantha
X
Ambros
Victor
V
D000818:Animals; D017173:Caenorhabditis elegans / Q000254:growth & development* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004777:Environment; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D008024:Ligands; D035683:MicroRNAs / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013997:Time Factors
D029742:Caenorhabditis elegans Proteins; C410905:DAF-12 protein, C elegans; D008024:Ligands; D035683:MicroRNAs; D018160:Receptors, Cytoplasmic and Nuclear; C474488:let-7 microRNA, C elegans