Let-7-complex microRNAs regulate the temporal identity of Drosophila mushroom body neurons via chinmo.

Many neural lineages display a temporal pattern, but the mechanisms controlling the ordered production of neuronal subtypes remain unclear. Here, we show that Drosophila let-7 and miR-125, cotranscribed from the let-7-Complex (let-7-C) locus, regulate the transcription factor chinmo to control temporal cell fate in the mushroom body (MB) lineage. We find that let-7-C is activated in postmitotic neurons born during the larval-to-pupal transition, when transitions among three MB subtypes occur. Loss or increase of let-7-C delays or accelerates these transitions, respectively, and leads to cell fate transformations. Consistent with our identification of let-7 and miR-125 sites in a recently identified ∼6 kb extension of the chinmo 3' UTR, Chinmo is elevated in let-7-C mutant MBs. In addition, we show that let-7-C acts upstream of chinmo and that let-7-C phenotypes are caused by elevated chinmo. Thus, these heterochronic miRNAs, originally identified in C. elegans, underlie progenitor cell multipotency during the development of diverse bilateria.