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lin-28  is a conserved regulator of cell fate succession in animals. In  Caenorhabditis elegans , it is a component of the heterochronic gene pathway that governs larval developmental timing, while its vertebrate homologs promote pluripotency and control differentiation in diverse tissues. The RNA binding protein encoded by  lin-28  can directly inhibit let-7 microRNA processing by a novel mechanism that is conserved from worms to humans. We found that  C. elegans  LIN-28 protein can interact with four distinct let-7 family pre-microRNAs, but in vivo inhibits the premature accumulation of only let-7. Surprisingly, however,  lin-28  does not require  let-7  or its relatives for its characteristic promotion of second larval stage cell fates. In other words, we find that the premature accumulation of mature let-7 does not account for  lin-28 's precocious phenotype. To explain  let-7 's role in  lin-28  activity, we provide evidence that  lin-28  acts in two steps: first, the  let-7 –independent positive regulation of  hbl-1  through its 3′UTR to control L2 stage-specific cell fates; and second, a  let-7 –dependent step that controls subsequent fates via repression of  lin-41 . Our evidence also indicates that  let-7  functions one stage earlier in  C. elegans  development than previously thought. Importantly,  lin-28 's two-step mechanism resembles that of the heterochronic gene  lin-14 , and the overlap of their activities suggests a clockwork mechanism for developmental timing. Furthermore, this model explains the previous observation that mammalian  Lin28  has two genetically separable activities. Thus,  lin-28 's two-step mechanism may be an essential feature of its evolutionarily conserved role in cell fate succession.

lin-28 Controls the Succession of Cell Fate Choices via Two Distinct Activities