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Tsutomu Kume, Seungwoon Seo; Conditional Inactivation of Foxc2 in Neural Crest Cells Leads to Corneal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2011;52(14):6408.
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Foxc2, a member of the forkhead/Fox transcription factor family, is a critical regulator of vascular development. Foxc2 is expressed in ocular mesenchymes of neural crest origin. Mutations of human FOXC2 are dominantly associated with Lymphedema-distichiasis syndrome. However, little is known about the role of Foxc2 in ocular development, mainly due to the mid-gestation lethality of Foxc2-/- mutants. Therefore, we investigate the role of Foxc2 in neural crest-derived cells (NCC) during ocular development.
Conditional mutant mice for Foxc2 were generated by crossing Foxc2fl mice with Wnt1-Cre mice to make tissue-specific deletion of Foxc2 specifically in the neural crest lineage. Corneal flat mounts in NCC-specific Foxc2 mice were performed to analyze the blood and lymphatic vessel formation using immunofluorescence for CD31 and/or LYVE1 antibodies. Phenotypic defects in the anterior segment were also examined by histological analyses.
Conventional Foxc2-/- mutants exhibit blood vessel formation in the peripheral corneal stroma at E15.5. NCC-specific Foxc2 mutant mice (4 wk-old) are much smaller in body size than control mice. NCC-specific Foxc2 mutant mice exhibit corneal neovascularization and lymphangiogenesis with complete penetrance. Mutant eyes exhibit abnormal thickness in the peripheral-to-central corneal stroma and limbus. Interestingly, some of mutant corneas have hyperplastic stroma with increased cell density. Mutant pupils are displaced from the normal central position. The anterior chamber is normally formed in both Foxc2-/- mutant and NCC-specific Foxc2 mutant mice.
The results suggest that the cell-autonomous function of Foxc2 in the neural crest plays an important role in maintaining corneal avascularity.
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