Loss of FOXC1 contributes to the corneal epithelial fate switch and pathogenesis.
Loss of FOXC1 contributes to the corneal epithelial fate switch and pathogenesis.
复制标题
FOXC1 缺失导致角膜上皮命运转换和发病机制
DOI：
10.1038/s41392-020-00378-2
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发表时间：
2021-01-08
影响因子：
39.3
通讯作者：
Ouyang H
中科院分区：
文献类型：
--
作者：
Li M;Zhu L;Liu J;Huang H;Guo H;Wang L;Li L;Gu S;Tan J;Zhong J;Wang B;Mao Z;Fan Y;Liu C;Yuan J;Ouyang H
叉头盒C1（FOXC 1）是神经嵴和眼发育所必需的，FOXC 1的突变导致遗传性阿克森-里格综合征。在这里，我们发现FOXC 1和配对盒6（PAX 6）在人类利姆布斯和中央角膜上皮共表达。FOXC 1缺陷和上皮特征的改变发生在角膜溃疡患者中。FOXC 1通过直接结合H3 K4 me 2标记的谱系特异性开放启动子或增强子来控制角膜上皮的命运。FOXC 1缺失不仅激活角质化途径并将角膜上皮细胞重编程为皮肤样上皮细胞，而且还破坏胶原代谢过程和干扰素信号传导途径。FOXC 1功能障碍引起的干扰素调节因子1和PAX 6的缺失与角膜溃疡有关。总的来说，我们的研究结果揭示了FOXC 1介导的调节网络负责角膜上皮稳态，并提供了一个潜在的治疗角膜溃疡的目标。
Forkhead box C1 (FOXC1) is required for neural crest and ocular development, and mutations in FOXC1 lead to inherited Axenfeld–Rieger syndrome. Here, we find that FOXC1 and paired box 6 (PAX6) are co-expressed in the human limbus and central corneal epithelium. Deficiency of FOXC1 and alternation in epithelial features occur in patients with corneal ulcers. FOXC1 governs the fate of the corneal epithelium by directly binding to lineage-specific open promoters or enhancers marked by H3K4me2. FOXC1 depletion not only activates the keratinization pathway and reprograms corneal epithelial cells into skin-like epithelial cells, but also disrupts the collagen metabolic process and interferon signaling pathways. Loss of interferon regulatory factor 1 and PAX6 induced by FOXC1 dysfunction is linked to the corneal ulcer. Collectively, our results reveal a FOXC1-mediated regulatory network responsible for corneal epithelial homeostasis and provide a potential therapeutic target for corneal ulcer.