The planar cell polarity (PCP) is implicated in multiple human structural birth defects including heart defects, neural tube defects and hard of hearing. PCP originally refers to coordinated arrangement of cells in an epithelial plane, but it was later discovered that the same molecules involved in PCP also regulate cell movement in both epithelia and mesenchyme. The PI found in preliminary studies that loss of Tmem132a in the mouse leads to defects in neural tube closure and tail morphogenesis. More importantly, Tmem132a interacts genetically with a core PCP regulator, Vangl2, in neural tube formation. In this proposal, the PI will test the hypothesis that Tmem132a regulates convergent extension movement in neural tube formation in collaboration with Vangl2. He will reveal the underlying cellular mechanisms by investigating asymmetrical localization of known PCP regulators and cytoskeleton components, as well as cellular morphology in Tmem132a mutant neural and non-neural ectoderm cells. The PI will also perform biochemical and cell biological analyses to study the potential mechanisms by which Tmem132a regulates PCP pathway. He will determine whether Tmem132a affects the output of the core PCP signaling by examining the activation of JNK and Rho in Tmem132a mutant cells. He will then investigate the physical interaction between Tmem132a and core PCP regulators Celsr and Fzd. He will test the hypothesis that Tmem132a promotes the recruitment of core PCP regulators and F-actin to the adherens junction in cultured cells. Although the importance of PCP in embryonic morphogenesis has been well established, the molecular network responsible for establishing and maintaining PCP has been poorly understood. The proposed research will provide a new link between cell/cell interaction and cellular polarity determination and greatly advance the understanding of the mechanisms of PCP regulation and related structural birth defects.
Planar Cell Polarity (PCP) regulation is important for many developmental processes including heart development, neural tube closure and the sense of hearing. We found that the transmembrane protein Tmem132a worked together with a well-known PCP regulator Vangl2 to regulate neural tube closure. This study will test the hypothesis that Tmem132a is an important component of the PCP regulatory network, providing much needed insight into the etiology and potential early intervention of neural tube defects.
