FOXC1 modulates MYOC secretion through regulation of the exocytic proteins RAB3GAP1, RAB3GAP2 and SNAP25

The neurodegenerative disease glaucoma is one of the leading causes of blindness in the world. Glaucoma is characterized by progressive visual field loss caused by retinal ganglion cell (RGC) death. Both surgical glaucoma treatments and medications are available, however, they only halt glaucoma progression and are unable to reverse damage. Furthermore, many patients do not respond well to treatments. It is therefore important to better understand the mechanisms involved in glaucoma pathogenesis. Patients with Axenfeld-Rieger syndrome (ARS) offer important insight into glaucoma progression. ARS patients are at 50% risk of developing early onset glaucoma and respond poorly to treatments, even when surgical treatments are combined with medications. Mutations in the transcription factor FOXC1 cause ARS. Alterations in FOXC1 levels cause ocular malformations and disrupt stress response in ocular tissues, thereby contributing to glaucoma progression. In this study, using biochemical and molecular techniques, we show that FOXC1 regulates the expression of RAB3GAP1, RAB3GAP2 and SNAP25, three genes with central roles in both exocytosis and endocytosis, responsible for extracellular trafficking. FOXC1 positively regulates RAB3GAP1 and RAB3GAP2, while either increase or decrease in FOXC1 levels beyond its normal range results in decreased SNAP25. In addition, we found that FOXC1 regulation of RAB3GAP1, RAB3GAP2 and SNAP25 affects secretion of Myocilin (MYOC), a protein associated with juvenile onset glaucoma and steroid-induced glaucoma. The present work reveals that FOXC1 is an important regulator of exocytosis and establishes a new link between FOXC1 and MYOC-associated glaucoma.

神经退行性疾病青光眼（glaucoma）是全球最主要的致盲病因之一。青光眼以视网膜神经节细胞（retinal ganglion cell, RGC）死亡引发的进行性视野缺损为特征。目前临床可采用手术治疗与药物治疗手段，但仅能延缓青光眼进展，无法逆转已造成的损伤。此外，众多患者对现有治疗响应不佳。因此，深入阐明青光眼发病机制具有重要意义。
阿克森费尔德-里格尔综合征（Axenfeld-Rieger syndrome, ARS）患者为青光眼进展的研究提供了重要视角。ARS患者发生早发性青光眼的风险高达50%，即便联合手术与药物治疗，对现有疗法的响应仍较差。转录因子FOXC1的突变可引发ARS。FOXC1表达水平异常会导致眼部畸形，并破坏眼部组织的应激反应，进而促进青光眼进展。
本研究通过生物化学与分子生物学技术，证实FOXC1可调控RAB3GAP1、RAB3GAP2及SNAP25的表达——这三个基因在胞吐与胞吞过程中均发挥核心作用，负责细胞外物质转运。FOXC1对RAB3GAP1与RAB3GAP2呈正向调控；而当FOXC1表达水平超出正常范围（上调或下调）时，均会导致SNAP25表达水平降低。
此外，本研究还发现FOXC1对上述三个基因的调控会影响肌纤蛋白（Myocilin, MYOC）的分泌，而该蛋白与青少年型青光眼及糖皮质激素诱导性青光眼密切相关。本研究揭示FOXC1是胞吐过程的重要调控因子，并建立了FOXC1与MYOC相关青光眼之间的全新关联。