Progression of metazoans through different developmental programs requires temporal control that is achieved by molecules originating from endocrine tissues that diffuse throughout the whole body of the animal to coordinate program execution by activating cell specific gene expression patterns. These programs then define cascades of successive, distinct developmental stages or the choice between alternative fates for the same stage. A model for this developmental control is found in the nematode C. elegans, where environmental cues signal through insulin and TGF-beta cascades to regulate the daf-12/nuclear hormone receptor (NHR) ligand synthesis that then coordinates organism wide developmental timing and fate choice. For cell intrinsic aspects of C. elegans temporal control of development, microRNAs play an important role but their connection to organism wide endocrine control is unknown. This work shows how the DAF-12/NHR directly activates let-7 family microRNAs during the L3 stage to repress L2 stage activator hbl-1 to prevent L2 stage programs from reoccurring. The interaction of upstream transcription factors with the downstream cis-regulatory elements in promoters of the let-7 family microRNAs are further analyzed in detail and identify potential DAF-12 coregulators that might connect daf-12 endocrine signaling also to later stage developmental control. These observations are the first to integrate microRNAs into establishedendocrine signaling cascades. In addition they reveal specific details about how organism wide upstream, endocrine signaling pathways induce downstream cell intrinsic changes of gene expression and developmental progression. This work postulates a "molecular switch" that actively drives stage transitions, consisting of a NHR that directly activates microRNAs to actively repress mediators of old stages while directly activating translation of protein coding genes mediating the new stage.

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