Molecular and genetic studies using mice show that neural crest-derived cells give rise to the trabecular meshwork as well as the stroma and endothelium of the cornea and are critical for the formation of the anterior segment of the eye. A failure of the normal development of the anterior segment of the eye in humans leads to anomalies in the structure of the mature anterior segment, associated with an increased risk of glaucoma and corneal opacity. The transcription factor 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. Mutations in human FOXC1 are associated with autosomal-dominant Axenfeld-Rieger Syndrome (ARS), a disorder characterized by anterior segment defects, glaucoma and other extraocular anomalies. Foxc2, a closely related factor, is expressed in neural crest-derived periocular mesenchyme, and Foxc2 heterozygous and compound Foxc1;Foxc2 heterozygous mutant mice have similar defects such as iris abnormalities to those in Foxc1 heterozygous mutants. However, the exact role of Foxc2/FOXC2 with respect to Foxc1/FOXC1 during anterior segment development is still unknown. Our new data let to the central hypothesis that Foxc1 and Foxc2 have overlapping as well as distinct roles in development of the anterior segment of the eye and corneal avascularity. This hypothesis will be tested by: (1) analyzing the formation of the anterior segment of the eye in a series of neural crest- and mesoderm-specific Foxc mutants as well as Foxc2 knock-in mice, (2) elucidating corneal NV in a series of neural crest- and mesoderm-specific Foxc mutants as well as Foxc2 knock-in mice, and (3) defining the angiogenic properties of Foxc- mutant corneal keratocytes. Successful completion of the proposed experiments will provide valuable insight into the overlapping and unique roles of Foxc1 and Foxc2 in anterior segment development and corneal avascularity and into the fundamental mechanisms that lead to the development of therapeutic strategies designed to inhibit corneal NV.

Public Health Relevance

Inherited disorders of the anterior segment of the eye are common in humans, but their causes and underlying developmental mechanisms are poorly understood. It is clear that mutant mice provide useful models to elucidate the molecular and cellular mechanisms of anterior segment development and dysgenesis as well as corneal neovascularization. The proposed studies will significantly contribute to a better understanding of the causes of congenital defects associated with the anterior segment of the eye and gain insight into the cellular and molecular basis of related human diseases.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Mckie, George Ann
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Northwestern University at Chicago
Internal Medicine/Medicine
Schools of Medicine
United States
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Fatima, Anees; Culver, Austin; Culver, Ford et al. (2014) Murine Notch1 is required for lymphatic vascular morphogenesis during development. Dev Dyn 243:957-64
Liu, Wenzhong; Schultz, Kathryn M; Zhang, Kevin et al. (2014) In vivo corneal neovascularization imaging by optical-resolution photoacoustic microscopy. Photoacoustics 2:81-86
French, Curtis R; Seshadri, Sudha; Destefano, Anita L et al. (2014) Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease. J Clin Invest 124:4877-81
Koo, Hyun-Young; Kume, Tsutomu (2013) FoxC1-dependent regulation of vascular endothelial growth factor signaling in corneal avascularity. Trends Cardiovasc Med 23:1-4
Seo, Seungwoon; Singh, Hardeep P; Lacal, Pedro M et al. (2012) Forkhead box transcription factor FoxC1 preserves corneal transparency by regulating vascular growth. Proc Natl Acad Sci U S A 109:2015-20
Zhang, Jianghui; Fukuhara, Shigetomo; Sako, Keisuke et al. (2011) Angiopoietin-1/Tie2 signal augments basal Notch signal controlling vascular quiescence by inducing delta-like 4 expression through AKT-mediated activation of beta-catenin. J Biol Chem 286:8055-66