The Role of Planar Cell Polarity Signaling in Neuronal Migration

Thesis (Ph.D.)--University of Washington, 2015The planar cell polarity (PCP) pathway is a cell-contact mediated mechanism for transmitting polarity information between neighboring cells. PCP “core components” (Vangl, Fz, Pk, Dvl, and Celsr) are essential for a number of cell migratory events including the posterior migration of facial branchiomotor neurons (FBMNs) in the plane of the hindbrain neuroepithelium in zebrafish and mice. While the mechanism by which PCP signaling polarizes static epithelial cells is well understood, how PCP signaling controls highly dynamic processes like neuronal migration remains an important outstanding question given that PCP components have been implicated in a range of directed cell movements, particularly during vertebrate development. Here, I present evidence that PCP signaling is required both within FBMNs and in the hindbrain rhombomere 4 environment at the time when they initiate their migration. Correspondingly, I demonstrate planar polarized localization of PCP core components Vangl2 and Fzd3a in the hindbrain neuroepithelium, and transient localization of Vangl2 at the tips of retracting FBMN filopodia. Using high-resolution timelapse imaging of FBMNs in genetic chimeras I uncovered opposing cell-autonomous and non-cell-autonomous functions for Fzd3a and Vangl2 in regulating FBMN protrusive activity. Within FBMNs, Fzd3a is required to stabilize filopodia while Vangl2 has an antagonistic, destabilizing role. However, in the migratory environment Fzd3a acts to destabilize FBMN filopodia while Vangl2 has a stabilizing role. Together, my findings suggest a model in which PCP signaling between the planar polarized neuroepithelial environment and FBMNs directs migration by the selective stabilization of FBMN filopodia