title: The DAF-3 Smad protein antagonizes TGF-beta-related receptor signaling in the Caenorhabditis elegans dauer pathway.
abstract: Signals from TGF-beta superfamily receptors are transduced to the nucleus by Smad proteins, which transcriptionally activate target genes. In Caenorhabditis elegans, defects in a TGF-beta-related pathway cause a reversible developmental arrest and metabolic shift at the dauer larval stage. Null mutations in daf-3 suppress mutations in genes encoding this TGF-beta signal, its receptors, and associated Smad signal transduction proteins. daf-3 encodes a Smad protein that is most closely related to mammalian DPC4, and is expressed throughout development in many of the tissues that are remodeled during dauer development. DAF-4, the type II TGF-beta receptor in this pathway, is also expressed in remodeled tissues. These data suggest that the DAF-7 signal from sensory neurons acts as a neuroendocrine signal throughout the body to directly regulate developmental and metabolic shifts in tissues that are remodeled during dauer formation. A full-length functional DAF-3/GFP fusion protein is predominantly cytoplasmic, and this localization is independent of activity of the upstream TGF-beta-related pathway. However, this fusion protein is associated with chromosomes in mitotic cells, suggesting that DAF-3 binds DNA directly or indirectly. DAF-3 transgenes also interfere with dauer formation, perhaps attributable to a dosage effect. A truncated DAF-3/GFP fusion protein that is predominantly nuclear interferes with dauer formation, implying a role for DAF-3 in the nucleus. These data suggest that DAF-7 signal transduction antagonizes or modifies DAF-3 Smad activity in the nucleus to induce reproductive development; when DAF-7 signals are disabled, unmodified DAF-3 Smad activity mediates dauer arrest and its associated metabolic shift. Therefore, daf-3 is unique in that it is antagonized, rather than activated, by a TGF-beta pathway.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114 USA.
authors.forename: G I
authors.initials: GI
authors.lastname: Patterson
authors.forename: A
authors.initials: A
authors.lastname: Koweek
authors.forename: A
authors.initials: A
authors.lastname: Wong
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.forename: G
authors.initials: G
authors.lastname: Ruvkun
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins; D002467:Cell Nucleus / Q000502:physiology; D003360:Cosmids; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D015723:Gene Library; D015801:Helminth Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D008322:Mammals; D008954:Models, Biological; D008969:Molecular Sequence Data; D010802:Phylogeny; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000737:chemistry / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051785:Smad Proteins; D015534:Trans-Activators; D014158:Transcription, Genetic
chemical_list: D029742:Caenorhabditis elegans Proteins; C108738:DAF-3 protein, C elegans; D004268:DNA-Binding Proteins; D015801:Helminth Proteins; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; D051785:Smad Proteins; D015534:Trans-Activators; C083704:daf-4 protein, C elegans