title: lin-28 controls the succession of cell fate choices via two distinct activities.
abstract: 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.
authors.affiliation: Department of Molecular Biology, University of Medicine and Dentistry of New Jersey, Stratford, New Jersey, United States of America.
authors.forename: Bhaskar
authors.initials: B
authors.lastname: Vadla
authors.forename: Kevin
authors.initials: K
authors.lastname: Kemper
authors.forename: Jennifer
authors.initials: J
authors.lastname: Alaimo
authors.forename: Christian
authors.initials: C
authors.lastname: Heine
authors.forename: Eric G
authors.initials: EG
authors.lastname: Moss
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D007814:Larva / Q000235:genetics / Q000254:growth & development; D035683:MicroRNAs; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D029742:Caenorhabditis elegans Proteins; D004268:DNA-Binding Proteins; D035683:MicroRNAs; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C102669:LIN-14 protein, C elegans; C452195:LIN-28 protein, C elegans; C410586:LIN-41 protein, C elegans; C474486:hbl-1 protein, C elegans; C474488:let-7 microRNA, C elegans