Vangl2-environment interaction causes severe neural tube defects, without abnormal neuroepithelial convergent extension.

Oleksandr Nychyk,Dawn Savery,Andrew J Copp,Matteo Molè,Philip Stanier,Gabriel L Galea,Nicholas D E Greene

doi:10.1242/dmm.049194

Oleksandr Nychyk, Dawn Savery + Show 5 more

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https://doi.org/10.1242/dmm.049194

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Abstract

ABSTRACTPlanar cell polarity (PCP) signalling is vital for initiation of mouse neurulation, with diminished convergent extension (CE) cell movements leading to craniorachischisis, a severe neural tube defect (NTD). Some humans with NTDs also have PCP gene mutations but these are heterozygous, not homozygous as in mice. Other genetic or environmental factors may interact with partial loss of PCP function in human NTDs. We found that reduced sulfation of glycosaminoglycans interacts with heterozygosity for the Lp allele of Vangl2 (a core PCP gene), to cause craniorachischisis in cultured mouse embryos, with rescue by exogenous sulphate. We hypothesized that this glycosaminoglycan–PCP interaction may regulate CE, but, surprisingly, DiO labelling of the embryonic node demonstrates no abnormality of midline axial extension in sulfation-depleted Lp/+ embryos. Positive-control Lp/Lp embryos show severe CE defects. Abnormalities were detected in the size and shape of somites that flank the closing neural tube in sulfation-depleted Lp/+ embryos. We conclude that failure of closure initiation can arise by a mechanism other than faulty neuroepithelial CE, with possible involvement of matrix-mediated somite expansion, adjacent to the closing neural tube.

Highlights

Neurulation is the series of embryonic events that gives rise to the closed neural tube (NT), the precursor of the brain and spinal cord
Planar cell polarity (PCP) signalling is vital for initiation of mouse neurulation, with diminished convergent extension (CE) cell movements leading to craniorachischisis, a severe neural tube defect (NTD)
Other genetic or environmental factors may interact with partial loss of PCP function in human NTDs

Summary

Introduction

Neurulation is the series of embryonic events that gives rise to the closed neural tube (NT), the precursor of the brain and spinal cord. Failure of NT closure at any level of the body axis leads to neural tube defects (NTDs), in which the neural plate remains open and subsequently degenerates, resulting in loss of neural function below that body level (Copp et al, 2015). Such defects are prominent causes of perinatal mortality and postnatal disability in humans, with NTDs affecting 1 per 1000 pregnancies on average worldwide, and with much higher frequencies in some geographical locations (Zaganjor et al, 2016). Failure of Closure 1 generates the most severe type of NTD, craniorachischisis (CRN), in which the neural tube remains open from midbrain to low spine (Copp et al, 1994), a defect that comprises around 10% of human NTDs, with a larger proportion in areas of high overall NTD prevalence (Moore et al, 1997)

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