Abstract
Post-zygotic mutations that generate tissue mosaicism are increasingly associated with severe congenital defects, including those arising from failed neural tube closure. Here we report that neural fold elevation during mouse spinal neurulation is vulnerable to deletion of the VANGL planar cell polarity protein 2 (Vangl2) gene in as few as 16% of neuroepithelial cells. Vangl2-deleted cells are typically dispersed throughout the neuroepithelium, and each non-autonomously prevents apical constriction by an average of five Vangl2-replete neighbours. This inhibition of apical constriction involves diminished myosin-II localisation on neighbour cell borders and shortening of basally-extending microtubule tails, which are known to facilitate apical constriction. Vangl2-deleted neuroepithelial cells themselves continue to apically constrict and preferentially recruit myosin-II to their apical cell cortex rather than to apical cap localisations. Such non-autonomous effects can explain how post-zygotic mutations affecting a minority of cells can cause catastrophic failure of morphogenesis leading to clinically important birth defects.
Highlights
Post-zygotic mutations that generate tissue mosaicism are increasingly associated with severe congenital defects, including those arising from failed neural tube closure
We recently reported that targeted deletion of Vangl[2] by Grhl3Cre in a proportion of neuroepithelial cells and throughout the surface ectoderm causes distal spina bifida[14]
We find that VANGL planar cell polarity protein 2 (Vangl2)-deleted cells prevent multiple neighbours from recruiting myosin-II to their cell cortex, thereby diminishing the apical constriction of a majority of neuroepithelial cells
Summary
Post-zygotic mutations that generate tissue mosaicism are increasingly associated with severe congenital defects, including those arising from failed neural tube closure. Vangl2-deleted neuroepithelial cells themselves continue to apically constrict and preferentially recruit myosin-II to their apical cell cortex rather than to apical cap localisations Such non-autonomous effects can explain how post-zygotic mutations affecting a minority of cells can cause catastrophic failure of morphogenesis leading to clinically important birth defects. Neural tube (NT) defects such as spina bifida continue to affect an average of 1:1000 pregnancies globally, with higher disease burden in developing countries[1]. They arise due to failure of NT closure in the early embryo[2]. Heterozygous PCP gene mutations have been associated with spina bifida in humans[9,17], the mechanisms linking such genetic findings with failed NT closure are unclear
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