Abstract
The planar cell polarity (PCP) pathway is a conserved non-canonical (β-catenin-independent) branch of Wnt signaling crucial to embryogenesis, during which it regulates cell polarity and polarized cell movements. Disruption of PCP components in mice, including Vangl2 and Dact1, results in defective neural tube closure and other developmental defects. Here, we show that Sestd1 is a novel binding partner of Vangl2 and Dact1. The Sestd1-Dact1 interface is formed by circumscribed regions of Sestd1 (the carboxyl-terminal region) and Dact1 (the amino-terminal region). Remarkably, we show that loss of Sestd1 precisely phenocopies loss of Dact1 during embryogenesis in mice, leading to a spectrum of birth malformations, including neural tube defects, a shortened and/or curly tail, no genital tubercle, blind-ended colons, hydronephrotic kidneys, and no bladder. Moreover, as with Dact1, a knock-out mutation at the Sestd1 locus exhibits reciprocal genetic rescue interactions during development with a semidominant mutation at the Vangl2 locus. Consistent with this, examination of Wnt pathway activities in Sestd1 mutant mouse embryonic tissue reveals disrupted PCP pathway biochemistry similar to that characterized in Dact1 mutant embryos. The Sestd1 protein is a divergent member of the Trio family of GTPase regulatory proteins that lacks a guanine nucleotide exchange factor domain. Nonetheless, in cell-based assays the Sestd1-Dact1 interaction can induce Rho GTPase activation. Together, our data indicate that Sestd1 cooperates with Dact1 in Vangl2 regulation and in the PCP pathway during mammalian embryonic development.
Highlights
Dact1 and Vangl2 regulate the planar cell polarity (PCP) pathway during development
In studies using genetically engineered mice, we have shown previously that Dact1 is required for normal post-translational regulation of Vangl2 during the epithelial-mesenchymal transition at the primitive streak, for normal PCP in posterior embryonic tissues, and that defects in these developmental processes in Dact1 null embryos lead to complex birth malformations, including neural tube defects (NTDs) [29]
PCP Pathway Abnormalities in SEC14 and spectrin domains-1 (Sestd1) Mutant Embryonic Tissue—We previously showed that the Dact1 mutant phenotypic spectrum, which we observe in Sestd1 mutant embryos, closely correlates with altered PCP but not altered Wnt/-catenin signaling in affected tissues of mutant embryos [29]
Summary
Dact and Vangl regulate the planar cell polarity (PCP) pathway during development. Results: Sestd genetically and biochemically interacts with Dact and Vangl and mediates PCP. Conclusion: Sestd cooperates with Dact to regulate Vangl and PCP. Disruption of PCP components in mice, including Vangl and Dact, results in defective neural tube closure and other developmental defects. We show that loss of Sestd precisely phenocopies loss of Dact during embryogenesis in mice, leading to a spectrum of birth malformations, including neural tube defects, a shortened and/or curly tail, no genital tubercle, blind-ended colons, hydronephrotic kidneys, and no bladder. Consistent with this, examination of Wnt pathway activities in Sestd mutant mouse embryonic tissue reveals disrupted PCP pathway biochemistry similar to that characterized in Dact mutant embryos. Our data indicate that Sestd cooperates with Dact in Vangl regulation and in the PCP pathway during mammalian embryonic development
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