Data from: The core planar cell polarity gene, Vangl2, directs adult corneal epithelial cell alignment and migration

This study shows that the core planar cell polarity (PCP) genes direct the aligned cell migration in the adult corneal epithelium, a stratified squamous epithelium on the outer surface of the vertebrate eye. Expression of multiple core PCP genes was demonstrated in the adult corneal epithelium. PCP components were manipulated genetically and pharmacologically in human and mouse corneal epithelial cells in vivo and in vitro. Knockdown of VANGL2 reduced the directional component of migration of human corneal epithelial (HCE) cells without affecting speed. It was shown that signalling through PCP mediators, dishevelled, dishevelled-associated activator of morphogenesis and Rho-associated protein kinase directs the alignment of HCE cells by affecting cytoskeletal reorganization. Cells in which VANGL2 was disrupted tended to misalign on grooved surfaces and migrate across, rather than parallel to the grooves. Adult corneal epithelial cells in which Vangl2 had been conditionally deleted showed a reduced rate of wound-healing migration. Conditional deletion of Vangl2 in the mouse corneal epithelium ablated the normal highly stereotyped patterns of centripetal cell migration in vivo from the periphery (limbus) to the centre of the cornea. Corneal opacity owing to chronic wounding is a major cause of degenerative blindness across the world, and this study shows that Vangl2 activity is required for directional corneal epithelial migration.

本研究证实，核心平面细胞极性（planar cell polarity，PCP）基因可调控成年角膜上皮——一种覆盖脊椎动物眼球外表面的复层鳞状上皮——的定向细胞迁移。研究人员在成年角膜上皮中检测到多种核心PCP基因的表达。随后，他们在体内和体外对人源及小鼠角膜上皮细胞的PCP组分进行了遗传与药理学操控。实验发现，敲低VANGL2会降低人角膜上皮（HCE）细胞迁移的定向性，但不影响其迁移速度。进一步研究表明，通过PCP介导分子散乱蛋白（dishevelled）、散乱蛋白相关形态发生激活因子以及Rho相关蛋白激酶介导的信号通路，可通过调控细胞骨架重排来指导HCE细胞的定向排列。当VANGL2被干扰后，细胞倾向于在沟槽表面错位排列，并横向而非平行于沟槽方向迁移。条件性敲除Vangl2的成年角膜上皮细胞，其创伤愈合迁移速率显著降低。在小鼠角膜上皮中条件性敲除Vangl2，会完全消除体内正常的、高度刻板的从外周（角膜缘）向角膜中央的向心性细胞迁移模式。由于慢性创伤引发的角膜混浊是全球范围内退行性失明的主要诱因之一，本研究证实Vangl2的活性对于角膜上皮的定向迁移至关重要。