Environmental pheromone and endocrine signals correct heterochronic developmental phenotypes caused by insufficient expression of let-7 family microRNAs in C. elegans

Adverse environmental conditions can affect rates of animal developmental progression and lead to temporary developmental quiescence (diapause), exemplified by the dauer larva stage of the nematode Caenorhabditis elegans. Remarkably, patterns of cell division and temporal cell fate progression in C. elegans larvae are not affected by changes in developmental trajectory. However, the underlying physiological and gene regulatory mechanisms that ensure robust developmental patterning despite substantial plasticity in developmental progression are largely unknown. Here, we report that diapause-inducing environmental pheromone and endocrine signals correct heterochronic developmental cell lineage defects caused by insufficient expression of let-7 family microRNAs in C. elegans. Two conserved endocrine signaling pathways, DAF-7/TGF-{beta} and DAF-2/Insulin, that confer on the larva diapause/non-diapause alternative developmental trajectories, interact with the nuclear hormone receptor, DAF-12, to initiate and regulate a rewiring of the genetic circuitry controlling temporal cell fates. This rewiring includes: 1) repression of the DAF-12 ligand-activated expression of let-7 family microRNAs, and 2) engagement of a novel ligand-independent DAF-12 activity to downregulate the critical let-7 family target Hunchback-like-1 (HBL-1). This alternative HBL-1 downregulation program is responsible for correcting let-7 family insufficiency phenotypes and it requires the activities of certain heterochronic genes, lin-46, lin-4 and nhl-2, that are previously associated with an altered genetic program in post-diapause animals. Our results show how environmental pheromones and endocrine signaling pathways can coordinately regulate both developmental progression and cell fate transitions in C. elegans larvae under stress, so that the developmental schedule of cell fates remains unaffected by changes in developmental trajectory.