Mechanisms underlying the formation of the cornea and ocular surface epithelium

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The ocular surface consists of a single continuous layer of epithelium and all associated structures, including the surface and glandular epithelia of the cornea, conjunctiva, and limbus, as well as the lacrimal and meibomian glands. The ocular surface plays a central role in vision, and diseases and disorders of the ocular surface and cornea is a leading cause of vision problems. The development, establishment, and maintenance of the ocular surface depend on the precise control of genetic networks that are tightly regulated by mesenchymal-epithelial interactions at the cellular level. Importantly, neural crest (NC)-derived cells give rise to the corneal and eyelid mesenchyme and are crucial for formation of the ocular surface. The long-term goal of our lab is to elucidate the fundamental mechanisms that regulate the formation and maintenance of the ocular surface and to understand how disruption of these mechanisms lead to defects in the ocular surface and cornea. Inactivating mutations of human FOXC2 are responsible for the autosomal dominant syndrome Lymphedema-distichiasis, which is characterized by the obstruction of lymphatic drainage in the limbs and the growth of aberrant, extra eyelashes (distichiasis). We have completed preliminary experiments suggesting (1) that an NC-specific mutation of Foxc2 in mice leads to corneal conjunctivalization, ectopic corneal neovascularization, defects in meibomian gland development, and impaired ocular epithelial cell identity, and (2) that compound, NC-specific mutations of Foxc2 and a closely related gene, Foxc1, have more severe eye defects, including the complete absence of the cornea, accompanied by significant declines in the expression of another key developmental factor, Pitx2, and its downstream effector Dkk2, which antagonizes canonical Wnt signaling. Thus, our central hypothesis is that Foxc2 is required in NC-derived cells for corneal development and the establishment of ocular epithelial-cell identity. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Identify molecular and genetic networks that govern corneal development; 2) Define the mechanisms by which Foxc2 participates in the formation of corneal epithelial-cell identity. In summary, the proposed research is significant, because our findings will contribute significantly to a better understanding of the formation of the ocular surface and the establishment of corneal epithelial identity. This will have an important positive impact on patient care, because the completion of the proposed studies will likely lead to identification of new targets and therapeutic strategies for improving vision in affected patients.