Mechanisms of anterior segment development and corneal neovascularization

描述（由申请人提供）：小鼠分子和遗传学研究表明，神经嵴来源的细胞产生小梁网以及角膜的基质和内皮，对眼睛前段的形成至关重要。人类眼睛前段正常发育的失败导致成熟前段结构的异常，与青光眼和角膜混浊的风险增加有关。转录因子Foxc1在发育中的眼睛周围的神经嵴和中胚层源性眼周间质中表达。我们之前已经证明Foxc1的杂合和纯合零突变小鼠有许多眼部异常，包括缺乏前房和角膜内皮，虹膜营养不良和小梁网异常。人类FOXC1基因突变与常染色体显性Axenfeld-Rieger综合征（ARS）有关，ARS是一种以前段缺损、青光眼和其他眼外异常为特征的疾病。Foxc2是一个密切相关的因子，表达于神经嵴源性眼周间质，Foxc2杂合和复合Foxc1；Foxc2杂合突变小鼠与Foxc1杂合突变小鼠具有类似的缺陷，如虹膜异常。然而，在前段发育过程中，Foxc2/ Foxc2相对于Foxc1/ Foxc1的确切作用尚不清楚。我们的新数据支持中心假设，即Foxc1和Foxc2在眼睛前段和角膜血管的发育中具有重叠和不同的作用。这一假设将通过以下方法得到验证：(1)分析一系列神经嵴和中胚层特异性Foxc突变体以及Foxc2敲入小鼠眼睛前段的形成；(2)阐明一系列神经嵴和中胚层特异性Foxc突变体以及Foxc2敲入小鼠角膜NV；(3)确定Foxc突变体角膜角质细胞的血管生成特性。该实验的成功完成将为了解Foxc1和Foxc2在角膜前段发育和角膜无血管中的重叠和独特作用提供有价值的见解，并为开发旨在抑制角膜NV的治疗策略提供基本机制。

DESCRIPTION (provided by applicant): Molecular and genetic studies using mice show that neural crest-derived cells give rise to the trabecular meshwork as well as the stroma and endothelium of the cornea and are critical for the formation of the anterior segment of the eye. A failure of the normal development of the anterior segment of the eye in humans leads to anomalies in the structure of the mature anterior segment, associated with an increased risk of glaucoma and corneal opacity. The transcription factor Foxc1 is expressed in neural crest- and mesoderm-derived periocular mesenchyme surrounding the developing eye. We have previously shown that heterozygous and homozygous null mutant mice for Foxc1 have numerous ocular abnormalities, including lack of the anterior chamber and corneal endothelium, iris dystrophy and abnormalities of the trabecular meshwork. Mutations in human FOXC1 are associated with autosomal-dominant Axenfeld-Rieger Syndrome (ARS), a disorder characterized by anterior segment defects, glaucoma and other extraocular anomalies. Foxc2, a closely related factor, is expressed in neural crest-derived periocular mesenchyme, and Foxc2 heterozygous and compound Foxc1; Foxc2 heterozygous mutant mice have similar defects such as iris abnormalities to those in Foxc1 heterozygous mutants. However, the exact role of Foxc2/FOXC2 with respect to Foxc1/FOXC1 during anterior segment development is still unknown. Our new data let to the central hypothesis that Foxc1 and Foxc2 have overlapping as well as distinct roles in development of the anterior segment of the eye and corneal avascularity. This hypothesis will be tested by: (1) analyzing the formation of the anterior segment of the eye in a series of neural crest- and mesoderm-specific Foxc mutants as well as Foxc2 knock-in mice, (2) elucidating corneal NV in a series of neural crest- and mesoderm-specific Foxc mutants as well as Foxc2 knock-in mice, and (3) defining the angiogenic properties of Foxc- mutant corneal keratocytes. Successful completion of the proposed experiments will provide valuable insight into the overlapping and unique roles of Foxc1 and Foxc2 in anterior segment development and corneal avascularity and into the fundamental mechanisms that lead to the development of therapeutic strategies designed to inhibit corneal NV. PUBLIC HEALTH RELEVANCE: Inherited disorders of the anterior segment of the eye are common in humans, but their causes and underlying developmental mechanisms are poorly understood. It is clear that mutant mice provide useful models to elucidate the molecular and cellular mechanisms of anterior segment development and dysgenesis as well as corneal neovascularization. The proposed studies will significantly contribute to a better understanding of the causes of congenital defects associated with the anterior segment of the eye and gain insight into the cellular and molecular basis of related human diseases.