Congenital ocular malformations such as anophthalmia, microphthalmia and coloboma 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. Wnts belong to a family of secreted, highly conserved glycoproteins that control key processes during development, disease and regeneration. Wnt signaling is very complex; in mammals, 19 Wnts and 10 Frizzled receptors have been identified that can activate the canonical, Wnt/?-catenin pathway and two less well-defined non-canonical pathways, Wnt/Ca2+ and Planar Cell Polarity. This complexity is reflected by the different roles of Wnt signaling during eye development. In this proposal, we aim to address two important questions; 1) How does non-canonical Wnt signaling regulate early eye development? 2) What is the cellular mechanism by which Wnt signaling controls closure of the optic fissure? To begin to tease this apart, we are focusing on the function of Porcupine (Porcn) that mediates posttranslational modification of Wnts. Porcn is a membrane-bound O-acyltransferase that resides in the endoplasmatic reticulum and mediates palmitoylation critical for the secretion and signaling activity of Wnt ligands. The human disease Focal Dermal Hypoplasia (FDH, Goltz Syndrome) is an X-linked, rare dominant disorder caused by mutations in PORCN. About 20% of FDH patients exhibit microphthalmia, anophthalmia, and coloboma (MAC), among several other severe developmental defects. While Porcn mutations cause MAC, we have no current understanding how depletion of Porcn/Wnt results in severe ocular malformations such as anophthalmia and coloboma. Using temporal and tissue-specific inactivation of Porcn, identification of potential targets and diverse in vitro approaches, we propose to identify the cellular interactions regulating closure of the optic fissure (Aim 1), investigate the role of non-canonical Wnt signaling during eye field and optic vesicle formation (Aim 2).
In Aim 3, we will investigate the role of the small GTPase Cdc42 in optic vesicle evagination and optic cup morphogenesis. Our approach will identify novel roles for Wnt signaling during eye development that will be important for treatment and regenerative efforts. The etiology of anophthalmia and coloboma in humans is complex and can result from disruption of several factors. The studies proposed here will advance our knowledge toward an understanding of the cellular and molecular mechanisms controlling eye morphogenesis at the earliest stages and during closure of the optic fissure.
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 investigate the role of an extracellular signaling pathway (Wnt) that is disturbed in the human disease Focal Dermal Hypoplasia (Goltz Syndrome), resulting in severe ocular congenital defects. We propose to employ mouse models to investigate how abnormalities in cellular interactions lead to severe ocular malformations during embryonic development.
| Pathak, Amrita; Stanley, Emily M; Hickman, F Edward et al. (2018) Retrograde Degenerative Signaling Mediated by the p75 Neurotrophin Receptor Requires p150Glued Deacetylation by Axonal HDAC1. Dev Cell 46:376-387.e7 |
| Yang, Yu-Ping; Ma, Haiting; Starchenko, Alina et al. (2017) A Chimeric Egfr Protein Reporter Mouse Reveals Egfr Localization and Trafficking In Vivo. Cell Rep 19:1257-1267 |
| Alldredge, Ashley; Fuhrmann, Sabine (2016) Loss of Axin2 Causes Ocular Defects During Mouse Eye Development. Invest Ophthalmol Vis Sci 57:5253-5262 |
| Bankhead, Elizabeth J; Colasanto, Mary P; Dyorich, Kayla M et al. (2015) Multiple requirements of the focal dermal hypoplasia gene porcupine during ocular morphogenesis. Am J Pathol 185:197-213 |
