Forkhead box transcription factor FoxC1 preserves corneal transparency by regulating vascular growth

Abstract

Normal vision requires the precise control of vascular growth to maintain corneal transparency. Here we provide evidence for a unique mechanism by which the Forkhead box transcription factor FoxC1 regulates corneal vascular development. Murine Foxc1 is essential for development of the ocular anterior segment, and in humans, mutations have been identified in Axenfeld-Rieger syndrome, a disorder characterized by anterior segment dysgenesis. We show that FOXC1 mutations also lead to corneal angiogenesis, and that mice homozygous for either a global (Foxc1

Studies on Axenfeld–Rieger syndrome patients and mice reveal Foxc1's role in corneal neovascularization

“…1B). This hypothesis is supported by data in figure S3D in the study by Seo et al (1), where iris smooth muscle cell differentiation is impaired in NC-Foxc1 −/− mutant mice. This concept is also reinforced by previous reports suggesting that forkhead genes (foxc1 and foxc2) can act as molecular switches to induce either paraaxial or intermediate mesoderm cell fate in vertebrate organogenesis (9).…”

“…FOXC1, PITX2, and PAX6 genes have been implicated in the etiology of ARS (3). Seo et al (1) identify that ARS patients with FOXC1 gene deletions or duplications showed pathological corneal angiogenesis consistent with previous findings on the role of FOXC1 gene dosage in mammalian ocular and CNS development (4). In mice, Foxc1 is expressed in the NCs that make up the cornea, as well as in the blood vessels.…”

“…All these factors act as proangiogenic/lymphangiogenic factors. The study by Seo et al (1) suggests that Foxc1 acts as an inhibitory factor for ECs, because mutation in the Foxc1 gene led to neovascularization of the cornea. Interestingly, a phenocopy of the Foxc1 mutation is also observed in the loss of Sox-F function (Fig.…”

“…Consequently, there is intense interest in understanding the processes that normally restrict blood vessel growth into the cornea. In PNAS, Seo et al (1) provide compelling evidence from human and mouse studies that implicate one member of the large Forkhead box (Fox) transcription factor family [Forkhead box transcription factor c1 (Foxc1)] in the regulation of corneal avascularity. Specifically, they suggest that Foxc1 regulates the normal delicate balance between factors in the cornea that can promote angiogenesis (e.g., VEGF and VEGF receptor) and those that inhibit growth of blood vessels and lymphatics (e.g., soluble VEGF receptor).…”

“…The study by Seo et al (1) sheds light on the interplay between neural crest cells (NCs) and endothelial cells (ECs) in the limbus, and its implications for corneal vascularity associated with the rare autosomal dominant disorder Axenfeld-Rieger syndrome (ARS) in humans. Some patients with ARS develop defects in their teeth, heart, and abdominal region, as well as in their eyes.…”