title: The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans.
abstract: The C. elegans heterochronic gene pathway consists of a cascade of regulatory genes that are temporally controlled to specify the timing of developmental events. Mutations in heterochronic genes cause temporal transformations in cell fates in which stage-specific events are omitted or reiterated. 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. 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.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, and Harvard Medical School, Boston 02114, USA.
authors.forename: B J
authors.initials: BJ
authors.lastname: Reinhart
authors.forename: F J
authors.initials: FJ
authors.lastname: Slack
authors.forename: M
authors.initials: M
authors.lastname: Basson
authors.forename: A E
authors.initials: AE
authors.lastname: Pasquinelli
authors.forename: J C
authors.initials: JC
authors.lastname: Bettinger
authors.forename: A E
authors.initials: AE
authors.lastname: Rougvie
authors.forename: H R
authors.initials: HR
authors.lastname: Horvitz
authors.forename: G
authors.initials: G
authors.lastname: Ruvkun
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D017173:Caenorhabditis elegans / Q000235:genetics / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins; D018509:DNA, Helminth; D004268:DNA-Binding Proteins / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D017238:Genes, Helminth; D005812:Genes, Switch; D008969:Molecular Sequence Data; D014176:Protein Biosynthesis; D018510:RNA, Helminth / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000502:physiology*; D013489:Suppression, Genetic; D014157:Transcription Factors / Q000235:genetics
chemical_list: D029742:Caenorhabditis elegans Proteins; D018509:DNA, Helminth; D004268:DNA-Binding Proteins; C095571:LIN-29 protein, C elegans; D018510:RNA, Helminth; D012333:RNA, Messenger; D014157:Transcription Factors