The regulation of developmental timing in Caenorhabditis elegans

The Caenorhabditis elegans heterochronic gene pathway consists of a regulatory hierarchy that coordinately controls the temporal identities of diverse types of postembryonic cells. Mutations in heterochronic genes cause temporal transformations in cell fate in which stage-specific events are either omitted with subsequent events occurring prematurely, or reiterated at the expense of later events.;lin-14 plays a central role in the progression from early to late larval development. lin-14 directs two distinct temporal fates, L1 fate determination and L2 timing, and these two genetic activities not only act at different points in development but are independently mutable. The lin-14 locus produces three novel, nuclearly localized proteins, and molecular characterization of lin-14 alleles that cause the specific loss of L2 fates has shown that L2 fate determination is provided by the LIN-14B1/B2 isoforms. No temporal differences in isoform expression have been detected, making it unlikely that the stage-specific phenotypes are due to distinct temporal expression profiles of the isoforms. However, genetic experiments suggested that a single isoform can be sufficient for normal development. Expression of LIN-14 appears to be simply reduced in lin-14(b-) mutants, suggesting that the level of lin-14 activity is crucial for fate determination.;At the end of the first larval stage, the lin-14 products are negatively regulated via their 3' UTR by the 22 nt lin-4 RNA to allow progression to L2 and later stages of development. Few genes involved in the subsequent progression through late larval stages have been identified, but new candidates were isolated in a screen for suppressors of egl-35; lin-14. Mutations in one gene, let-7, cause animals to reiterate late larval fates and delay the onset of the adult stage. Positional cloning of let-7 identified a 21 nt untranslated RNA as the gene product. The 3' UTRs of several heterochronic genes contain sequences complementary to the let-7 RNA, suggesting that let-7 physically interacts with these mRNAs. Genetic and molecular experiments support our theory that let-7 acts in the heterochronic pathway. A model is proposed whereby sequential stage-specific expression of the lin-4 and let-7 regulatory RNAs trigger transitions in the expression of heterochronic genes to allow developmental progression.