Functional interaction between Vangl2 and N-cadherin regulates the planar cell polarization of neural tissues

Abstract Although the core constituents of the Wnt/planar cell polarity (PCP) signaling have been extensively studied, their downstream molecules and protein–protein interactions have not yet been fully elucidated. Here, we show genetic and molecular evidence that the PCP factor, Vangl2, functionally interacts with the cell–cell adhesion molecule, N-cadherin (also known as Cdh2), for typical PCP-dependent neural development. Vangl2 and N-cadherin physically interact in the neural plates undergoing convergent extension. Unlike monogenic heterozygotes, digenic heterozygous mice with Vangl2 and Cdh2 mutants exhibited defects in neural tube closure and cochlear hair cell orientation. Neuroepithelial cells derived from digenic heterozygotes did not show any significant changes in the RhoA–Mypt1 or c-Jun N-terminal kinase (JNK)–Jun pathways of Wnt/PCP signaling. Thus, cooperation between Vangl2 and N-cadherin is at least partly via direct molecular interaction; it is independent of both RhoA and JNK pathways and essential for the polarized development of neural tissues.