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05-01-2012 | Genetics | Article

FoxC1 gene prevents corneal vascularization, maintains transparency


Free abstract

MedWire News: Researchers have found that the forkhead box transcription factor gene (FoxC1) inhibits corneal angiogenesis, thereby playing an important role in the maintenance of corneal transparency.

Normal vision requires the regulation of vascular growth to maintain corneal transparency. Multiple eye disorders linked to blindness are caused by excessive corneal vascular growth.

"We believe we've discovered the master regulator gene that prevents the formation of blood vessels in the eye and protects the clarity of the cornea," said lead study author Tsutomu Kume (Northwestern University, Chicago, Illinois, USA) in an associated press release.

Kume and team found that mice lacking the FoxC1 gene showed extensively vascularized corneas, a perturbed extracellular matrix (ECM), and elevated levels of several pro-angiogenic matrix-metalloproteinases (MMPs), including MMP3, MMP9, and MMP19.

"Since MMP-mediated ECM degradation is involved in pathological neovascularization, this process may lead to the outgrowth of blood and lymphatic vessels from the limbus," comments the team in the Proceedings of the National Academy of Sciences.

Furthermore, mice with a neural crest (NC)-specific FoxC1 mutation showed similar characteristics to those with a global mutation, suggesting that FoxC1 in the NC plays a specific role during ocular development.

Mice with only one copy of the FoxC1 gene showed normal corneal vasculature, although limbal vasculature was disrupted and the growth of vessels after corneal alkali burn injury was enhanced. Inhibition of vascular endothelial growth factor (VEGF) prevented the amplification of the angiogenic response.

Following these findings, the researchers identified that patients who had a single copy of the mutated FoxC1 gene - and also had congenital glaucoma -showed abnormal corneal angiogenesis.

The authors say the phenotypic observations in patients coupled with the findings in mice support the theory of a complementary mechanism that maintains corneal transparency through the FoxC1-mediated regulation of ECM alterations and subsequent VEGF-mediated angiogenesis.

"The exciting thing is by showing the loss of FoxC1 causes vascularization of the cornea, it means increasing levels of the gene might help prevent the abnormal growth of blood vessels, potentially in multiple eye disorders that cause blindness," said study co-author Ordan Lehmann (University of Alberta, Canada) in the press release.

Indeed, Lehmann said the findings could be used to treat growth of new blood vessels onto transplanted corneas. Studies are underway to test the gene therapy in mice and ascertain whether injecting FoxC1 inhibits corneal angiogenesis.

By Ingrid Grasmo

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