Suriben Rowena, Kivimäe Saul, Fisher Daniel A C, Moon Randall T, Cheyette Benjamin N R
Department of Psychiatry, University of California, San Francisco, San Francisco, California, USA.
Nat Genet. 2009 Sep;41(9):977-85. doi: 10.1038/ng.435. Epub 2009 Aug 23.
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.
Dact1（也称为Dapper或Frodo）发生突变的纯合小鼠表现出与人类脊柱、泌尿生殖系统和远端消化道畸形相似的表型。我们将这种表型追溯到原条处胚层形态发生的破坏。值得注意的是，平面细胞极性（PCP）途径的跨膜成分Vangl2的杂合突变挽救了隐性Dact1表型，而Dact1的缺失则相反地挽救了半显性Vangl2表型。我们发现，细胞内蛋白Dact1与Vangl2形成复合物。在Dact1突变体中，Vangl2在原条处增加，而细胞通常在此处经历上皮-间充质转化。这与E-钙黏蛋白分布异常以及PCP途径的生化指标变化有关。我们得出结论，Dact1通过在细胞黏附和PCP途径上游调节Vangl2，对原条处的形态发生起作用。
