The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans

The C. elegans heterochronic gene pathway consists of a cascade of regulato ry genes that are temporally controlled to specify the timing of developmen tal events(1). Mutations in heterochronic genes cause temporal transformati ons in cell fates in which stage-specific events are omitted or reiterated( 2). Here we show that let-7 is a heterochronic switch gene. Loss of let-7 g ene activity causes reiteration of larval cell fates during the adult stage , whereas increased let-7 gene dosage causes precocious expression of adult fates during larval stages. let-7 encodes a temporally regulated 21-nucleo tide RNA that is complementary to elements in the 3' untranslated regions o f the heterochronic genes lin-14, lin-28, lin-41, lin-42 and daf-12, indica ting that expression of these genes may be directly controlled by let-7. A reporter gene bearing the lin-41 3' untranslated region is temporally regul ated in a let-7-dependent manner. A second regulatory RNA, lin-4, negativel y regulates lin-14 and lin-28 through RNA-RNA interactions with their 3' un translated regions(3,4). We propose that the sequential stage-specific expr ession of the lin-4 and let-7 regulatory RNAs triggers transitions in the c omplement of heterochronic regulatory proteins to coordinate developmental timing.