Uveal coloboma represents one of the most common congenital ocular malformations accounting for up to 10% of childhood blindness (~1 in 5000 live birth). Coloboma originates from defective fusion of the optic fissure (OF), a transient gap that forms during eye morphogenesis by asymmetric, ventral invagination. Genetic heterogeneity combined with the activity of developmentally regulated genes suggests multiple mechanisms regulating OF closure. The tumor suppressor and FERM domain protein Neurofibromin 2 (NF2) controls diverse processes in cancer, development and regeneration, via Hippo pathway and cytoskeleton regulation. In humans, NF2 mutations can cause ocular abnormalities, including coloboma, however, its actual role in OF closure is unknown. Using conditional inactivation in the embryonic mouse eye, our data indicate that loss of Nf2 function results in a novel underlying cause for coloboma. In particular, mutant eyes show substantially increased retinal pigmented epithelium (RPE) proliferation in the fissure region with concomitant acquisition of RPE cell fate. Cells lining the OF margin can maintain RPE fate ectopically and fail to transition from neuroepithelial to cuboidal shape. In the dorsal RPE of the optic cup, Nf2 inactivation leads to a robust increase in cell number, with local disorganization of the cytoskeleton components F-actin and pMLC2. We propose that RPE hyperproliferation is the primary cause for the observed defects causing insufficient alignment of the OF margins in Nf2 mutants and failure to fuse properly, resulting in persistent coloboma. Our findings indicate that limiting proliferation particularly in the RPE layer is a critical mechanism during OF closure.

中文翻译：

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Nf2在胚胎小鼠眼视裂闭合过程中微调增殖和组织排列

葡萄膜缺损是最常见的先天性眼部畸形之一，占儿童失明的 10%（每 5000 例活产中约有 1 例）。Coloboma 起源于视裂 (OF) 的有缺陷的融合，这是一种在眼睛形态发生过程中通过不对称、腹侧内陷形成的短暂间隙。遗传异质性与发育调节基因的活性相结合，表明调节 OF 关闭的多种机制。肿瘤抑制因子和 FERM 结构域蛋白神经纤维蛋白 2 (NF2) 通过 Hippo 通路和细胞骨架调节控制癌症、发育和再生的不同过程。在人类中，NF2突变可导致眼部异常，包括缺损，但是，其在 OF 闭合中的实际作用尚不清楚。在胚胎小鼠眼中使用条件失活，我们的数据表明Nf2功能的丧失导致缺损的新潜在原因。特别是，突变的眼睛显示裂隙区域视网膜色素上皮 (RPE) 增殖显着增加，同时获得 RPE 细胞命运。OF 边缘的细胞可以异位地维持 RPE 的命运，并且无法从神经上皮细胞转变为立方体形状。在视杯的背侧 RPE 中，Nf2失活导致细胞数量大幅增加，细胞骨架成分 F-肌动蛋白和 pMLC2 局部解体。我们认为 RPE 过度增殖是观察到的缺陷的主要原因，该缺陷导致Nf2突变体中OF 边缘对齐不足以及无法正确融合，从而导致持续性缺损。我们的研究结果表明，限制增殖尤其是在 RPE 层中是 OF 关闭过程中的一个关键机制。