Pryor, SE; (2013) Planar cell polarity signalling and development of the early mammalian nervous system. Doctoral thesis (PhD), UCL (University College London).

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Abstract

The vertebrate planar cell polarity (PCP) pathway is an evolutionarily conserved signalling cascade which regulates numerous developmental processes. This thesis investigates the role of PCP signalling in two events, mammalian spinal neurulation and neural crest (NC) cell migration. In mouse embryos PCP signalling is required for initiation of neural tube closure, via regulation of midline convergent extension (CE). In this thesis, a genetic modifying role for the loop-tail (Vangl2Lp) mutation is shown to also predispose to failure of low spinal neurulation. Mutations in the core PCP gene Vangl2 increase the frequency and severity of spina bifida in the grainyhead-like-3 hypomorph curly tail (Grhl3ct/ct), a model of partially-penetrant NTDs. Affected Vangl2Lp/+;Grhl3ct/ct embryos exhibit abnormalities of axis elongation, suggesting a role for CE in spinal neurulation. Investigations of the mechanism underlying the Lp/ct interaction reveal two distinct types of effect: 1) Effects of expression of Vangl2Lp and Grhl3ct in different tissues: Vangl2 regulates midline CE and Grhl3 regulates proliferation of tail bud progenitors. These mutant effects likely summate, leading to severe spina bifida; 2) Cell-autonomous effects of Vangl2Lp and Grhl3ct co-expression in the same tissue: conditional genetic experiments suggest a requirement for Vangl2 and Grhl3 within the same cells during neurulation and evidence for a molecular interaction at the level of Rho-GTPase signalling is presented. In amphibia and fish, early NC migration is PCP-dependent, but this has not yet been studied in mammals. Vangl2Lp/Lp embryos display normal NC cell migration, despite many severe PCP-related defects, and migration of Vangl2Lp/Lp NC in vitro is comparable to Vangl2+/+. The closely related gene Vangl1 does not appear to compensate for loss of Vangl2. Acute down-regulation of Vangl2 specifically in the NC lineage does not cause migratory defects. Hence, the core PCP pathway is not required for early NC migration in the mouse.

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