Cell non-autonomy amplifies disruption of neurulation by mosaic Vangl2 deletion in mice.
Cell non-autonomy amplifies disruption of neurulation by mosaic Vangl2 deletion in mice.
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DOI：
10.1038/s41467-021-21372-4
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发表时间：
2021-02-19
影响因子：
16.6
通讯作者：
Copp AJ
中科院分区：
文献类型：
--
作者：
Galea GL;Maniou E;Edwards TJ;Marshall AR;Ampartzidis I;Greene NDE;Copp AJ
产生组织嵌合体的合子后突变越来越多地与严重的先天性缺陷有关，包括那些由神经管关闭失败引起的缺陷。在这里，我们报道了在小鼠脊髓神经形成过程中，只有16%的神经上皮细胞中VANGL平面细胞极性蛋白2(Vangl2)基因的缺失容易导致神经折叠的抬高。Vangl2缺失的细胞通常分散在神经上皮细胞中，每个非自主的细胞通过平均5个Vangl2缺失的相邻细胞来阻止心尖收缩。这种对心尖收缩的抑制包括减少相邻细胞边界上的肌球蛋白-II的定位和缩短基底部延伸的微管尾巴，这是已知的促进心尖收缩的因素。Vangl2缺失的神经上皮细胞本身继续在顶端收缩，并优先将肌球蛋白-II招募到它们的顶端细胞皮质，而不是顶端。这种非自主效应可以解释合子后突变如何影响少数细胞，导致灾难性的形态发生失败，从而导致临床上重要的出生缺陷。已在患有严重先天性缺陷的个体中发现了导致组织嵌合体的突变。在这里，作者表明，小鼠神经上皮细胞中Vangl2的镶嵌缺失通过减少肌球蛋白II和微管蛋白组织来防止心尖收缩，从而导致脊柱裂。
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.
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影响因子：
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