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Posterior malformations in Dact1 mutant mice arise through misregulated Vangl2 at the primitive streak.

Nature genetics | Sep 27, 2009

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.

Pubmed ID: 19701191 RIS Download

Mesh terms: Alleles | Amino Acid Sequence | Animals | Congenital Abnormalities | Conserved Sequence | Crosses, Genetic | Gene Expression Regulation, Developmental | Homozygote | Intracellular Signaling Peptides and Proteins | Mice | Mice, Inbred C57BL | Mice, Mutant Strains | Molecular Sequence Data | Mutation | Nerve Tissue Proteins | Primitive Streak | Protein Structure, Tertiary

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Associated grants

  • Agency: NIMH NIH HHS, Id: K08MH001750
  • Agency: NIMH NIH HHS, Id: K08 MH001750-03
  • Agency: NICHD NIH HHS, Id: R01 HD055300-02
  • Agency: NIMH NIH HHS, Id: K08 MH001750-05
  • Agency: NICHD NIH HHS, Id: R01 HD055300-03
  • Agency: NICHD NIH HHS, Id: R01HD055300
  • Agency: NIMH NIH HHS, Id: K08 MH001750
  • Agency: NIMH NIH HHS, Id: K08 MH001750-04
  • Agency: NICHD NIH HHS, Id: R01 HD055300
  • Agency: NICHD NIH HHS, Id: R01 HD055300-01

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