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Updated: Jun 20, 2026
In Vivo Modeling of the Morbid Human Genome using Danio rerio
Published on: August 24, 2013
Posterior malformations in Dact1 mutant mice arise through misregulated Vangl2 at the primitive streak
Rowena Suriben1, Saul Kivimäe, Daniel A C Fisher
1Department of Psychiatry, University of California, San Francisco, San Francisco, California, USA.
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.
Insights
Dapper 1 (Dact1) mutations cause developmental defects by disrupting early embryonic morphogenesis. Dact1 interacts with Vangl2 to regulate cell adhesion and planar cell polarity during development.
Area of Science:
- Developmental Biology
- Genetics
- Molecular Biology
Background:
- Mutations in Dapper 1 (Dact1) in mice lead to malformations mirroring human conditions affecting the spine, genitourinary, and digestive systems.
- These phenotypes are linked to disruptions in germ-layer morphogenesis at the primitive streak stage of embryonic development.
Purpose of the Study:
- To investigate the molecular mechanisms by which Dact1 influences embryonic morphogenesis.
- To elucidate the relationship between Dact1 and the planar cell polarity (PCP) pathway.
Main Methods:
- Genetic rescue experiments using heterozygous mutations in Vangl2.
- Biochemical analysis of protein complex formation between Dact1 and Vangl2.
- Assessment of Vangl2 localization, E-cadherin distribution, and PCP pathway markers in Dact1 mutant mice.
Main Results:
- Heterozygous Vangl2 mutations rescued Dact1 phenotypes, and Dact1 loss rescued Vangl2 phenotypes, indicating a functional interaction.
- Dact1 physically complexes with Vangl2, an intracellular protein.
- Dact1 deficiency leads to increased Vangl2 at the primitive streak, affecting epithelial-mesenchymal transition, E-cadherin distribution, and PCP pathway activity.
Conclusions:
- Dact1 regulates Vangl2 activity upstream of cell adhesion and the PCP pathway.
- Dact1 is crucial for proper morphogenesis at the primitive streak by modulating Vangl2.
- This study reveals a novel regulatory role for Dact1 in embryonic development and PCP signaling.
