title: 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(-/-)) or neural crest (NC)-specific (NC-Foxc1(-/-)) null mutation display excessive growth of corneal blood and lymphatic vessels. This is associated with disorganization of the extracellular matrix and increased expression of multiple matrix metalloproteinases. Heterozygous mutants (Foxc1(+/-) and NC-Foxc1(+/-)) exhibit milder phenotypes, such as disrupted limbal vasculature. Moreover, environmental exposure to corneal injury significantly increases growth of both blood and lymphatic vessels in both Foxc1(+/-) and NC-Foxc1(+/-) mice compared with controls. Notably, this amplification of the angiogenic response is abolished by inhibition of VEGF receptor 2. Collectively, these findings identify a role for FoxC1 in inhibiting corneal angiogenesis, thereby maintaining corneal transparency by regulating VEGF signaling.
authors.affiliation: Feinberg Cardiovascular Research Institute, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Seungwoon
authors.initials: S
authors.lastname: Seo
authors.forename: Hardeep P
authors.initials: HP
authors.lastname: Singh
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Lacal
authors.forename: Amy
authors.initials: A
authors.lastname: Sasman
authors.forename: Anees
authors.initials: A
authors.lastname: Fatima
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Schultz
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Losordo
authors.forename: Ordan J
authors.initials: OJ
authors.lastname: Lehmann
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kume
mesh_terms: D000468:Alkalies; D000818:Animals; D000869:Anterior Eye Segment / Q000002:abnormalities / Q000378:metabolism / Q000473:pathology; D001808:Blood Vessels / Q000254:growth & development* / Q000473:pathology; D002056:Burns / Q000473:pathology; D003315:Cornea / Q000098:blood supply* / Q000473:pathology; D003319:Corneal Stroma / Q000201:enzymology / Q000473:pathology; D005124:Eye Abnormalities / Q000150:complications / Q000378:metabolism / Q000473:pathology; D015785:Eye Diseases, Hereditary; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D057895:Haploinsufficiency / Q000235:genetics; D006579:Heterozygote; D042583:Lymphangiogenesis; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D009432:Neural Crest / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011680:Pupil; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000468:Alkalies; D051858:Forkhead Transcription Factors; C112890:Foxc1 protein, mouse; D042461:Vascular Endothelial Growth Factor A; D020782:Matrix Metalloproteinases