Investigation of Notch signaling in the regulation of ciliary body development and function

Stowers Institute For Medical Research, Kansas City MO

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Abstract

Project Summary Anterior segment dysgenesis (ASD) refers to a spectrum of disorders affecting the structures in the anterior segment of the eye, including the iris, ciliary body (CB), cornea and trabecular meshwork. Approximately, 50% of the patients with ASD develop glaucoma. It can be also accompanied by other systemic defects, such as Alagille syndrome. However, the molecular and cellular mechanisms underlying ASD remain largely elusive. This proposed study is designed to investigate the developmental mechanisms underlying the morphogenesis of the CB, a part of the anterior segment. The CB has two important biological functions: lens accommodation and secretion of aqueous humor for maintaining intraocular pressure (IOP). High IOP is associated with the risk for glaucoma, whereas defective lens accommodation causes myopia or near-sightedness. The long-term goal of this project is to gain a greater understanding of how Notch signaling controls normal CB morphogenesis and secretion. This proposed study is based on our recent exciting finding that Notch2 controls CB morphogenesis, which was published in PNAS (2013). Our unpublished preliminary findings demonstrate that Notch2 and BMP signaling maintain the expression of RhoA in the CB, and that RhoA is also important for CB morphogenesis. Three specific aims of this proposed study are: (1) to investigate if Jag1 and Dll1 activate Notch2 and Notch3 to control CB morphogenesis; (2) to investigate how Notch-regulated BNP signaling controls CB morphogenesis by promoting RhoA protein expression in the OCE; (3) to investigate if Dll1-Notch3 signaling controls CB secretion through Rbpj-dependent mechanisms. Defective Jag1-Notch2 signaling causes Alagille syndrome, which affects the anterior segment of the eye, liver, lung and vasculature in humans, but the underlying cellular mechanisms remain largely unknown. Therefore, this proposed study would enhance our ability to understand the molecular and cellular mechanisms underlying the pathogenesis of glaucoma, myopia and Alagille Syndrome, and would help find better treatments for the diseases.