title: Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development.
abstract: Dishevelled (Dvl) proteins are important signaling components of both the canonical beta-catenin/Wnt pathway, which controls cell proliferation and patterning, and the planar cell polarity (PCP) pathway, which coordinates cell polarity within a sheet of cells and also directs convergent extension cell (CE) movements that produce narrowing and elongation of the tissue. Three mammalian Dvl genes have been identified and the developmental roles of Dvl1 and Dvl2 were previously determined. Here, we identify the functions of Dvl3 in development and provide evidence of functional redundancy among the three murine Dvls. Dvl3(-/-) mice died perinatally with cardiac outflow tract abnormalities, including double outlet right ventricle and persistent truncus arteriosis. These mutants also displayed a misorientated stereocilia in the organ of Corti, a phenotype that was enhanced with the additional loss of a single allele of the PCP component Vangl2/Ltap (LtapLp/+). Although neurulation appeared normal in both Dvl3(-/-) and LtapLp/+ mutants, Dvl3(+/-);LtapLp/+ combined mutants displayed incomplete neural tube closure. Importantly, we show that many of the roles of Dvl3 are also shared by Dvl1 and Dvl2. More severe phenotypes were observed in Dvl3 mutants with the deficiency of another Dvl, and increasing Dvl dosage genetically with Dvl transgenes demonstrated the ability of Dvls to compensate for each other to enable normal development. Interestingly, global canonical Wnt signaling appeared largely unaffected in the double Dvl mutants, suggesting that low Dvl levels are sufficient for functional canonical Wnt signals. In summary, we demonstrate that Dvl3 is required for cardiac outflow tract development and describe its importance in the PCP pathway during neurulation and cochlea development. Finally, we establish several developmental processes in which the three Dvls are functionally redundant.
authors.affiliation: Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA.
authors.forename: S Leah
authors.initials: SL
authors.lastname: Etheridge
authors.forename: Saugata
authors.initials: S
authors.lastname: Ray
authors.forename: Shuangding
authors.initials: S
authors.lastname: Li
authors.forename: Natasha S
authors.initials: NS
authors.lastname: Hamblet
authors.forename: Nardos
authors.initials: N
authors.lastname: Lijam
authors.forename: Michael
authors.initials: M
authors.lastname: Tsang
authors.forename: Joy
authors.initials: J
authors.lastname: Greer
authors.forename: Natalie
authors.initials: N
authors.lastname: Kardos
authors.forename: Jianbo
authors.initials: J
authors.lastname: Wang
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sussman
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Anthony
authors.initials: A
authors.lastname: Wynshaw-Boris
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003051:Cochlea / Q000196:embryology* / Q000378:metabolism; D000072261:Dishevelled Proteins; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis; D009206:Myocardium / Q000378:metabolism; D054259:Neural Tube / Q000196:embryology* / Q000378:metabolism; D009436:Neural Tube Defects / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000606578:DVL1 protein, human; C000606581:DVL2 protein, human; C000606584:DVL3 protein, human; D000072261:Dishevelled Proteins; C000606579:Dvl1 protein, mouse; C000606582:Dvl2 protein, mouse; C000606585:Dvl3 protein, mouse; D010750:Phosphoproteins; D051153:Wnt Proteins