Congenital ocular malformations such as microphthalmia, anophthalmia and coloboma (MAC) are prevalent in ~1 in 3-4,000 individuals and are the cause for over 25% of childhood blindness worldwide. Coloboma alone may account up to 10% of childhood blindness. Therefore, it is vitally important to understand the molecular mechanisms underlying ocular development. While several causative genes are identified, more effort is required to define the downstream targets and events underlying eye morphogenesis. Mutations in the Porcupine gene (PORCN) cause the human disease Focal Dermal Hypoplasia (FDH, Goltz Syndrome), an X-linked dominant multisystem birth defect associated with (MAC). Porcn is an O-acyltransferase that mediates palmitoylation of Wnts, a large family of secreted, highly conserved glycoproteins that activate distinct pathways, the canonical Wnt/-catenin pathway and two less well-defined non-canonical pathways, Wnt/Ca2+ and Planar Cell Polarity. Temporally controlled and tissue-specific inactivation in mouse revealed that Porcn is required early for evagination and regionalization of the optic vesicle and later for closure of the optic fissure. Using genetic mouse models, RNAseq and culture approaches, we propose to determine the role of Porcn and Wnt pathways in regulating cell-cell interactions during closure of the optic fissure (Aim 1).
In Aim 2, we will investigate the role of Porcn and non-canonical Wnt signaling during eye field development and morphogenesis of the optic vesicle. Furthermore, the Rho GTPase Cdc42 is a key regulator of cell junction assembly and actin cytoskeleton, acting downstream of distinct signaling pathways, including non-canonical Wnt signaling.
In Aim 3, we propose to investigate the role of Cdc42 in regulating morphogenesis of the optic vesicle and optic cup. The studies proposed here will be a critical step toward an understanding of the cellular and molecular mechanisms controlling eye morphogenesis and important for advancing treatment and regenerative efforts of ocular diseases.

Public Health Relevance

Microphthalmia (small eye), anophthalmia (absence of eye) and coloboma (defect in closure of the optic fissure) are severe congenital ocular birth defects that can cause up to 25% of childhood blindness worldwide. To understand the cause of the birth defects and develop therapeutic strategies, knowledge of the mechanisms regulating eye development is essential. The goal of the proposed research is to define the role of the Wnt activator Porcupine that is mutated in the human disease Focal Dermal Hypoplasia (Goltz Syndrome), resulting in severe ocular congenital defects. Furthermore, we will determine the roles of distinct Wnt signaling pathways and of the Rho GTPase Cdc42 during different stages of ocular morphogenesis. We propose to employ genetic mouse models and in vitro approaches to elucidate the cellular and molecular mechanisms underlying morphogenesis of the eye during embryonic development.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (BVS)
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Greenwell, Thomas
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Vanderbilt University Medical Center
Schools of Medicine
United States
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