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T. Kume, S. Seo; The Forkhead Transcription Factor Foxc1 is Required for Corneal Avascularity. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6424.
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© ARVO (1962-2015); The Authors (2016-present)
Corneal avascularity is tightly controlled to establish the transparency of the cornea; however, the basic mechanisms of how pro-angiogenic and anti-angiogenic signals are regulated in the corneal stroma remain largely unknown. Mutations in the transcription factor FOXC1 are associated with autosomal-dominant Axenfeld-Rieger Syndrome (ARS), a disorder characterized by anterior segment defects, glaucoma and other extraocular anomalies. Murine 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.
To determine the role of Foxc1 in neural crest-derived stroma in the cornea, we have analyzed newly generated neural crest-specific Foxc1 mutant mice.
Our new data show that conditional inactivation of Foxc1 in the neural crest in mice leads to similar ocular defects as seen in conventional Foxc1 mutant embryos. Remarkably, conventional and neural crest-specific Foxc1 mutants have ectopic neovascularization in the corneal stroma starting at embryonic day 15.5 (E15.5), whereas endothelial-specific Foxc1 mutants have normal, avascular corneas. We have also found abnormal formation of lymphatic vessels (lymphangiogenesis) in the cornea of neural crest-specific Foxc1 mutants. Gene expression profiling revealed that mRNA expression of particular angiogenic genes, including several MMPs, Bmp2, Dkk2, and sFlt1, is differentially regulated in Foxc1-mutant corneas, while VEGF-A and VEGF-C remain unchanged.
Our novel findings suggest that Foxc1 is required for corneal avascularity.
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