Grant: Operating Grant

Vangl proteins form multi-protein membrane complexes that provide positional information to cells. These Vangl complexes play a critical developmental role in establishing cell polarity in the plane of epithelia, in the positioning of cellular appendages such as motile cilia, in the formation of three dimensional structures such as tubules, and in cell movement and migration. These fundamental processes are essential to organogenesis. We have shown that mutations in Vangl genes cause neural tube defects such as spina and excencephaly in the Lp mouse mutant, and we have detected mutant VANGL1 and VANGL2 variants in clinical cases of human neural tube defects. We wish to study the mechanism by which mutations in VANGL1 and VANGL2 cause neural tube defects in humans; We also propose to identify the Vangl protein determinants responsible for different aspects of protein functions such as membrane targeting and assembly into membrane signaling complexes. We have created a conditional Vangl2 mutant that can be inactivated in a tissue and time-dependent fashion. We will use this mutant to study the role of Vangl2 in the structure and function of the retina and of the kidney, including a possible association with retinal degeneration and cystic kidney disease. We also propose a genetic approach in mice to identify genes in the Vangl2 pathway that may also be associated with NTD in humans.