Journal Article

Cell non-autonomy amplifies disruption of neurulation by mosaic Vangl2 deletion in mice

Ampartzidis, Ioakeim, Galea, Gabriel L., Copp, Andrew J., Edwards, Timothy J., Marshall, Abigail R., Maniou, Eirini, Greene, Nicholas D. E.

2021

Overview

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. Mutations that cause tissue mosaicism have been identified in individuals with severe congenital defects. Here, the authors show that mosaic deletion of Vangl2 in the murine neuroepithlium causes spina bifida by preventing apical constriction via reduced myosin II and tubulin organisation.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 14/19 / 14/34 / 14/35 / 14/63 / 631/136/1425 / 631/136/1660 / 631/80/128 / 64/60 / Actin Cytoskeleton - metabolism / Animals / Autonomy / Birth defects / Catastrophic events / Cell Polarity - physiology / Congenital defects / Constrictions / Disease Models, Animal / Gene Deletion / Humanities and Social Sciences / Mice / Morphogenesis / Morphogenesis - genetics / Morphogenesis - physiology / Mosaicism / Mosaics / multidisciplinary / Mutation / Myosin / Myosin Type II - metabolism / Nerve Tissue Proteins - genetics / Nerve Tissue Proteins - metabolism / Neural Crest - metabolism / Neural tube / Neural Tube Defects - genetics / Neuroepithelial Cells - metabolism / Neuroepithelial Cells - pathology / Neurulation - genetics / Neurulation - physiology / Polarity / Science / Science (multidisciplinary) / Spina bifida / Transcriptome / Tubulin