title: Dishevelled 2 is essential for cardiac outflow tract development, somite segmentation and neural tube closure.
abstract: The murine dishevelled 2 (Dvl2) gene is an ortholog of the Drosophila segment polarity gene Dishevelled, a member of the highly conserved Wingless/Wnt developmental pathway. Dvl2-deficient mice were produced to determine the role of Dvl2 in mammalian development. Mice containing null mutations in Dvl2 present with 50% lethality in both inbred 129S6 and in a hybrid 129S6-NIH Black Swiss background because of severe cardiovascular outflow tract defects, including double outlet right ventricle, transposition of the great arteries and persistent truncus arteriosis. The majority of the surviving Dvl2(-/-) mice were female, suggesting that penetrance was influenced by sex. Expression of Pitx2 and plexin A2 was attenuated in Dvl2 null mutants, suggesting a defect in cardiac neural crest development during outflow tract formation. In addition, approximately 90% of Dvl2(-/-) mice have vertebral and rib malformations that affect the proximal as well as the distal parts of the ribs. These skeletal abnormalities were more pronounced in mice deficient for both Dvl1 and Dvl2. Somite differentiation markers used to analyze Dvl2(-/-) and Dvl1(-/-);Dvl2(-/-) mutant embryos revealed mildly aberrant expression of Uncx4.1, delta 1 and myogenin, suggesting defects in somite segmentation. Finally, 2-3% of Dvl2(-/-) embryos displayed thoracic spina bifida, while virtually all Dvl1/2 double mutant embryos displayed craniorachishisis, a completely open neural tube from the midbrain to the tail. Thus, Dvl2 is essential for normal cardiac morphogenesis, somite segmentation and neural tube closure, and there is functional redundancy between Dvl1 and Dvl2 in some phenotypes.
authors.affiliation: Department of Pediatrics, UCSD Comprehensive Cancer Center, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0627, USA.
authors.forename: Natasha S
authors.initials: NS
authors.lastname: Hamblet
authors.forename: Nardos
authors.initials: N
authors.lastname: Lijam
authors.forename: Pilar
authors.initials: P
authors.lastname: Ruiz-Lozano
authors.forename: Jianbo
authors.initials: J
authors.lastname: Wang
authors.forename: Yasheng
authors.initials: Y
authors.lastname: Yang
authors.forename: Zhenge
authors.initials: Z
authors.lastname: Luo
authors.forename: Lin
authors.initials: L
authors.lastname: Mei
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Sussman
authors.forename: Anthony
authors.initials: A
authors.lastname: Wynshaw-Boris
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D000818:Animals; D001842:Bone and Bones / Q000002:abnormalities / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002356:Cartilage / Q000378:metabolism; D002454:Cell Differentiation; D003433:Crosses, Genetic; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D005091:Exons; D005260:Female; D005838:Genotype; D006321:Heart / Q000196:embryology* / Q000502:physiology; D006330:Heart Defects, Congenital / Q000235:genetics; D018398:Homeodomain Proteins / Q000096:biosynthesis; D015151:Immunoblotting; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008855:Microscopy, Electron, Scanning; D008957:Models, Genetic; D009154:Mutation; D009206:Myocardium / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009432:Neural Crest / Q000196:embryology* / Q000378:metabolism; D009687:Nuclear Proteins; D010641:Phenotype; D010750:Phosphoproteins / Q000378:metabolism; D011506:Proteins / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D014157:Transcription Factors / Q000096:biosynthesis; D000097577:Homeobox Protein PITX2
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D011506:Proteins; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2; C000606579:Dvl1 protein, mouse; C000606582:Dvl2 protein, mouse; C492113:Plxna2 protein, mouse; C000606588:dsh protein, Drosophila