title: Posterior malformations in Dact1 mutant mice arise through misregulated Vangl2 at the primitive streak.
abstract: Mice homozygous for mutations in Dact1 (also called Dapper or Frodo) phenocopy human malformations involving the spine, genitourinary system and distal digestive tract. We traced this phenotype to disrupted germ-layer morphogenesis at the primitive streak. Notably, heterozygous mutation of Vangl2, a transmembrane component of the planar cell polarity (PCP) pathway, rescued recessive Dact1 phenotypes, whereas loss of Dact1 reciprocally rescued semidominant Vangl2 phenotypes. We show that Dact1, an intracellular protein, forms a complex with Vangl2. In Dact1 mutants, Vangl2 was increased at the primitive streak, where cells ordinarily undergo an epithelial-mesenchymal transition. This is associated with abnormal E-cadherin distribution and changes in biochemical measures of the PCP pathway. We conclude that Dact1 contributes to morphogenesis at the primitive streak by regulating Vangl2 upstream of cell adhesion and the PCP pathway.
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Rowena
authors.initials: R
authors.lastname: Suriben
authors.forename: Saul
authors.initials: S
authors.lastname: Kivimäe
authors.forename: Daniel A C
authors.initials: DA
authors.lastname: Fisher
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.forename: Benjamin N R
authors.initials: BN
authors.lastname: Cheyette
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D000013:Congenital Abnormalities / Q000209:etiology* / Q000235:genetics; D017124:Conserved Sequence; D003433:Crosses, Genetic; D018507:Gene Expression Regulation, Developmental; D006720:Homozygote; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D054240:Primitive Streak; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431577:Ltap protein, mouse; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; C508545:frodo protein, mouse
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