title: Dominant gain-of-function mutations that lead to misregulation of the C. elegans heterochronic gene lin-14, and the evolutionary implications of dominant mutations in pattern-formation genes.
abstract: The heterochronic gene lin-14 controls the temporal sequence of developmental events in the C. elegans postembryonic cell lineage. It encodes a nuclear protein that is normally present in most somatic cells of late embryos and L1 larvae but not in later larval stages or adults. Two lin-14 gain-of-function mutations cause an inappropriately high level of the lin-14 nuclear protein late in development. These mutations delete 3' untranslated sequences from the lin-14 mRNAs and identify a negative regulatory element that controls the formation of the lin-14 protein temporal gradient. The 21 kb lin-14 gene contains 13 exons that are differentially spliced to generate two lin-14 protein products with variable N-terminal regions and a constant C-terminal region. No protein sequence similarity to any proteins in various databases was found. The temporal and cellular expression patterns of lin-14 protein accumulation is altered by mutations in the heterochronic genes lin-4 and lin-28. The lin-4 gene is required to down-regulate lin-14 protein levels during the mid-L1 stage. The lin-4 gene product could be the trans-acting factor that binds to the negative regulatory element in the lin-14 3' untranslated region. In contrast, the lin-28 gene activity positively regulates lin-14 protein levels during early L1. Thus, these genes act antagonistically to regulate the lin-14 temporal switch. The normal down-regulation of lin-14 within 10 h of hatching is not determined by the passage of time per se, but rather is triggered when feeding induces post-embryonic development.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston.
authors.forename: G
authors.initials: G
authors.lastname: Ruvkun
authors.forename: B
authors.initials: B
authors.lastname: Wightman
authors.forename: T
authors.initials: T
authors.lastname: Bürglin
authors.forename: P
authors.initials: P
authors.lastname: Arasu
mesh_terms: D000818:Animals; D005075:Biological Evolution; D002107:Caenorhabditis; D002454:Cell Differentiation / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D005799:Genes, Dominant / Q000502:physiology*; D008957:Models, Genetic; D009024:Morphogenesis / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics
chemical_list: D009687:Nuclear Proteins