title: Two genetic circuits repress the Caenorhabditis elegans heterochronic gene lin-28 after translation initiation.
abstract: The heterochronic gene lin-28 of the nematode Caenorhabditis elegans controls the relative timing of diverse developmental events during the animal's larval stages. lin-28 is stage-specifically regulated by two genetic circuits: negatively by the 22-nt RNA lin-4 and positively by the heterochronic gene lin-14. Here, we show that lin-28 is repressed during normal development by a mechanism that acts on its mRNA after translation initiation. We provide evidence that lin-14 inhibits a negative regulation that is independent of the lin-4 RNA and involves the gene daf-12, which encodes a nuclear hormone receptor. The lin-4-independent repression does not affect the initiation of translation on the lin-28 mRNA, and like the lin-4-mediated repression, acts through the gene's 3'-untranslated region. In addition, we find that lin-4 is not sufficient to cause repression of lin-28 if the lin-4-independent circuit is inhibited. Therefore, the lin-4-independent circuit likely contributes substantially to the down-regulation of lin-28 that occurs during normal development. The role of lin-4 may be to initiate or potentiate the lin-4-independent circuit. We speculate that a parallel lin-4-independent regulatory mechanism regulates the expression of lin-14.
authors.affiliation: Fox Chase Cancer Center, 7701 Burholme Avenue, Philadelphia, PA 19111, USA.
authors.forename: Kathy
authors.initials: K
authors.lastname: Seggerson
authors.forename: Lingjuan
authors.initials: L
authors.lastname: Tang
authors.forename: Eric G
authors.initials: EG
authors.lastname: Moss
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000254:growth & development; D029742:Caenorhabditis elegans Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D002499:Centrifugation, Density Gradient; D003513:Cycloheximide / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D015801:Helminth Proteins; D007814:Larva; D035683:MicroRNAs; D008957:Models, Genetic; D009687:Nuclear Proteins; D010441:Peptide Chain Elongation, Translational; D010442:Peptide Chain Initiation, Translational; D011499:Protein Processing, Post-Translational; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D012270:Ribosomes / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; C410905:DAF-12 protein, C elegans; D015801:Helminth Proteins; C102669:LIN-14 protein, C elegans; C452195:LIN-28 protein, C elegans; D035683:MicroRNAs; D009687:Nuclear Proteins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C452194:lin-4 microRNA, C elegans; D003513:Cycloheximide