The Planar Cell Polarity Protein Vangl2 is Crucial for Intraretinal Pathfinding of Retinal Ganglion Cell Axons
1. Complex Traits Group, 2. Department of Human Genetics, 3. Department of Biochemistry, McGill University; 4. Cellular Neurobiology Research Unit, Institut de Recherches Cliniques de Montréal; 5. Department of Medicine, McGill University Health Centre; 6. Faculty of Medicine, Université de Montréal.
Vangl2 plays a critical role in the establishment of planar cell polarity (PCP) and is well characterized for its role in human and murine neural tube development. In mice, we have previously detected expression of Vangl2 in the developing embryonic retina, which led us to investigate the potential role of Vangl2 during retinal development. We found that Vangl2 mRNA and protein are dynamically expressed in the developing retina, with Vangl2 expression becoming progressively restricted to the ganglion cell layer and optic nerve as the retina matures. Specifically, the expression of Vangl2 is most prominent at the plasma membrane and the axons of retinal ganglion cells (RGCs). Additionally, we have found that Vangl2 is essential for retinal and optic nerve development as Vangl2Lp/Lp mutant embryos display reduced eye size, thickening of the retina, and optic nerve hypoplasia. Notably, in Vangl2Lp/Lp mutant retinas, we observed axon bundles that traversed throughout the entire retina without specific orientation. These ectopic axons ultimately became trapped within the sub-retinal space leading to optic nerve hypoplasia. Moreover we found that the Lpassociated retinal phenotypes are not linked to increased RGC generation, progenitor proliferation, or retinal axon outgrowth. Taken together, these results identify a severe intraretinal pathfinding defect of RGC axons in Vangl2Lp/Lp embryos, highlighting a novel and essential role for Vangl2 in retinal axon guidance.