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Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development

Etheridge, SL and Ray, S and Li, S and Hamblet, NS and Lijam, N and Tsang, M and Greer, J and Kardos, N and Wang, J and Sussman, DJ and Chen, P and Wynshaw-Boris, A (2008) Murine dishevelled 3 functions in redundant pathways with dishevelled 1 and 2 in normal cardiac outflow tract, cochlea, and neural tube development. PLoS Genetics, 4 (11). ISSN 1553-7390

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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. © 2008 Etheridge et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Etheridge, SL
Ray, S
Li, S
Hamblet, NS
Lijam, N
Tsang, Mtsang@pitt.eduTSANG
Greer, J
Kardos, N
Wang, J
Sussman, DJ
Chen, P
Wynshaw-Boris, A
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorBeier, David R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 1 November 2008
Date Type: Publication
Journal or Publication Title: PLoS Genetics
Volume: 4
Number: 11
DOI or Unique Handle: 10.1371/journal.pgen.1000259
Refereed: Yes
ISSN: 1553-7390
PubMed Central ID: PMC2576453
PubMed ID: 19008950
Date Deposited: 24 Jul 2012 18:49
Last Modified: 29 Jan 2019 15:55
URI: http://d-scholarship.pitt.edu/id/eprint/13004

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