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PMID:19008950

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Citation

Etheridge, SL, Ray, S, Li, S, Hamblet, NS, Lijam, N, Tsang, M, Greer, J, Kardos, N, Wang, J, Sussman, DJ, 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 Genet. 4:e1000259

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.

Links

PubMed PMC2576453 Online version:10.1371/journal.pgen.1000259

Keywords

Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Animals; Cochlea/embryology; Cochlea/metabolism; Embryo, Mammalian/metabolism; Female; Heart/embryology; Heart Defects, Congenital/embryology; Heart Defects, Congenital/genetics; Heart Defects, Congenital/metabolism; Humans; Male; Mice; Mice, Knockout; Morphogenesis; Myocardium/metabolism; Neural Tube/embryology; Neural Tube/metabolism; Neural Tube Defects/embryology; Neural Tube Defects/genetics; Neural Tube Defects/metabolism; Phenotype; Phosphoproteins/genetics; Phosphoproteins/metabolism; Signal Transduction; Wnt Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:DVL1

involved_in

GO:0060070: canonical Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2137230

P

Seeded From UniProt

complete

MOUSE:DVL2

involved_in

GO:0090103: cochlea morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:108100

P

Seeded From UniProt

complete

MOUSE:DVL2

involved_in

GO:0003007: heart morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:108100

P

Seeded From UniProt

complete

MOUSE:DVL2

involved_in

GO:0060070: canonical Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2429760

P

Seeded From UniProt

complete

MOUSE:DVL3

involved_in

GO:0090103: cochlea morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:106613

P

Seeded From UniProt

complete

MOUSE:DVL3

involved_in

GO:0090103: cochlea morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2135272

P

Seeded From UniProt

complete

MOUSE:DVL3

involved_in

GO:0090179: planar cell polarity pathway involved in neural tube closure

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2135272

P

Seeded From UniProt

complete

MOUSE:DVL3

involved_in

GO:0060071: Wnt signaling pathway, planar cell polarity pathway

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2135272

P

Seeded From UniProt

complete

MOUSE:DVL3

involved_in

GO:0003007: heart morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:106613

P

Seeded From UniProt

complete

MOUSE:DVL3

involved_in

GO:0003148: outflow tract septum morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3831892

P

Seeded From UniProt

complete

MOUSE:VANG2

involved_in

GO:0090103: cochlea morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:108100

P

Seeded From UniProt

complete

MOUSE:VANG2

involved_in

GO:0090179: planar cell polarity pathway involved in neural tube closure

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:108100

P

Seeded From UniProt

complete

MOUSE:DVL2

acts_upstream_of_or_within

GO:0003007: heart morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:108100

P

has_participant:(EMAPA:16105)

Seeded From UniProt

complete

MOUSE:DVL2

acts_upstream_of_or_within

GO:0060070: canonical Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2429760

P

occurs_in:(EMAPA:16405)|occurs_in:(EMAPA:16184)|occurs_in:(EMAPA:16860)

Seeded From UniProt

complete

MOUSE:DVL2

acts_upstream_of_or_within

GO:0090103: cochlea morphogenesis

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:108100

P

Seeded From UniProt

complete


See also

References

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