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 β-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.

Syndecan 4 controls lymphatic vasculature remodeling during mouse embryonic development

“…In vertebrate inner ear hair cells, the core PCP proteins Frizzled (Fz) and Dishevelled (Dvl) form a complex on one side of the cell that is opposite to Van Gogh (Vangl) and Prickle (Pk) on the other. This asymmetric distribution of the PCP proteins is required for hair cell polarization (Deans et al, 2007;Etheridge et al, 2008;Montcouquiol et al, 2006;Wang et al, 2006;Yin et al, 2012). Increased Vangl2 levels in Sdc4 −/− LECs may disrupt PCP protein distribution in the cells, resulting in abnormal cellular orientation.…”

Role of chromatin remodeling gene Cecr2 in neurulation and inner ear development

“…Embryos deficient in Dvl2 show a low percentage of exencephaly and spina bifida, whereas most Dvl1 À/À ; Dvl2 À/À double mutants show craniorachischisis on a 129SvEv inbred strain and a mixed 129SvEv x NIH Black Swiss strain (Hamblet et al, 2002). Other combined mutations have also shown a percentage of exencephaly, including Dvl3 6 ; Vangl2 Lpþ (5 cranio, 2 exen /22), whereas Dvl3 À/À ; Vangl2 Lp/þ showed only craniorachischisis (6/16) on a mixed genetic background with 129S6 (Etheridge et al, 2008). Smurf ubiquitin ligases1 and 2, involved in degradation of the PCP core protein Prickle1, show exencephaly and/or spina bifida as well as inner ear defects in 25% of embryos which lose three of four Smurf alleles (Narimatsu et al, 2009).…”

Wnt Signaling in Mammalian Development: Lessons from Mouse Genetics

“…Indeed, in Looptail mutant mice (Vangl2 Lp/Lp ) that harbor a spontaneous loss-of-function mutation in Vangl2, the stereociliary orientation becomes randomized, suggesting that a conserved mammalian PCP pathway is required to coordinate stereociliary orientation among hair cells (Montcouquiol et al 2003). This hypothesis was validated by the findings of similar stereociliary orientation defects in mouse mutants of other PCP orthologs, including Celsr1 (an ortholog of flamingo [Curtin et al 2003]), Fz3 and -6 (Wang et al 2006b) and Dvl1, -2, and -3 (Wang et al 2005;Etheridge et al 2008). Furthermore, mouse PCP proteins display asymmetric plasma membrane distribution in the organ of Corti, and mutation of one PCP gene perturbs the membrane localization of other PCP proteins (Wang et al 2005(Wang et al , 2006bMontcouquiol et al 2006;Jones et al 2008).…”