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

The C. elegans heterochronic gene pathway consists of a cascade of regulatory genes that are temporally controlled to specify the timing of developmental events 1 . Mutations in heterochronic genes cause temporal transformations 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 gene 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-nucleotide RNA that is complementary to elements in the 3′ untranslated regions of the heterochronic genes lin-14 , lin-28 , lin-41 , lin-42 and daf-12 , indicating that expression of these genes may be directly controlled by let-7 . A reporter gene bearing the lin-41 3′ untranslated region is temporally regulated in a let-7 -dependent manner. A second regulatory RNA, lin-4 , negatively regulates lin-14 and lin-28 through RNA–RNA interactions with their 3′ untranslated regions 3 , 4 . We propose that the sequential stage-specific expression of the lin-4 and let-7 regulatory RNAs triggers transitions in the complement of heterochronic regulatory proteins to coordinate developmental timing.