Dact1 functions in the planar cell polarity pathway during vertebrate gastrulation

The Dact family (also known as Dapper/Frodo) of cytoplasmic scaffold proteins are expressed during embryonic development and have been shown to modulate developmentally important signaling pathways such as the Wnt pathway. To gain a better understanding of the developmental stages and tissues in which Dacts function, the embryonic expression pattern of the mouse Dact family was characterized. Dact1 is expressed in mesoderm derived tissue (i.e. presomitic mesoderm and somites) and in the primitive streak, where gastrulation occurs. To determine if Dact1 is required for gastrulation, mouse mutants in the Dact1 gene were analyzed during gastrulation stages (e7.0-e8.5). These data indicate that at the 6 somite stage, Dact1 mutants have posterior morphological defects in the region of the primitive streak reminiscent of phenotypes associated with abnormalities in convergent extension movements necessary to elongate the embryo. These posterior defects are associated with disruptions in downstream readouts of the Planar Cell Polarity Pathway and not the Wnt/beta-catenin pathway. The morphological differences seen in Dact1 mutants arise due to the abnormal upregulation of membrane Vangl2 and E-cadherin protein levels in primitive streak cells undergoing epithelial-mesenchymal transition (EMT) preceeding cell migration. Vangl2 Loop-tail mutants show the opposite effect with a reduction in Vangl2 membrane localization in these cells. Importantly, crossing these two mutations (i.e. making Dact1 mutants also heterozygous for the Vangl2 Loop-tail mutation) restored Vangl2 membrane levels at the primitive streak and rescued Dact1 embryological phenotypes. These data identify a role for Dact1 in regulating appropriate levels of the Planar Cell Polarity protein Vangl2 necessary for EMT and cell migration during mouse gastrulation.