Abstract
Anterior segment dysgenesis is often associated with cornea diseases, cataracts, and glaucoma. In the anterior segment, the ciliary body (CB) containing inner and outer ciliary epithelia (ICE and OCE) secretes aqueous humor that maintains intraocular pressure (IOP). However, CB development and function remain poorly understood. Here, this study shows that NOTCH signaling in the CB maintains the vitreous, IOP, and eye structures by regulating CB morphogenesis, aqueous humor secretion, and vitreous protein expression. Notch2 and Notch3 function via RBPJ in the CB to control ICE-OCE adhesion, CB morphogenesis, aqueous humor secretion, and protein expression, thus maintaining IOP and eye structures. Mechanistically, NOTCH signaling transcriptionally controls Nectin1 expression in the OCE to promote cell adhesion for driving CB morphogenesis and to directly stabilize Cx43 for controlling aqueous humor secretion. Finally, NOTCH signaling directly controls vitreous protein secretion in the ICE. Therefore, this study provides important insight into CB functions and involvement in eye diseases.
Highlights
The congenital developmental disorders affecting the anterior segment of the eye are collectively known as anterior segment dysgenesis (ASD), which is associated with 50% risk for glaucoma (Reis and Semina, 2011)
NOTCH2 and NOTCH3 Contribute to NOTCH-RBPJ Signaling for Controlling inner ciliary epithelium (ICE)-outer ciliary epithelium (OCE) Adhesion and ciliary body (CB) Fold Formation To understand why inactivating Recombination signal binding protein for immunoglobulin kappa J region (Rbpj) but not Notch2 in the retinal pigmented epithelium (RPE) causes eye degeneration (Sarode et al, 2014; Zhou et al, 2013), we reexamined the mutant phenotypes of the conditional Rbpj and Notch2 knockout eyes by using Tyrp2-Cre, which can efficiently delete a floxed gene throughout the iris, the CB, and the RPE (Davis et al, 2009; Figure S1)
The Rbpj mutant eyes frequently exhibit the self-folded ICE stem in the CB and the separated ICE folded on the top of the retina, which result from the separation of the ICE and the OCE in the developing CB, suggesting that RBPJ is required in the developing CB for maintaining ICE-OCE adhesion (Figures 1B’ and 1B’’)
Summary
The congenital developmental disorders affecting the anterior segment of the eye are collectively known as anterior segment dysgenesis (ASD), which is associated with 50% risk for glaucoma (Reis and Semina, 2011). As a part of the anterior segment, the ciliary body (CB) consists of three major components: nonpigmented inner ciliary epithelium (ICE), pigmented outer ciliary epithelium (OCE), and the underlying stroma and blood vessels (Beebe, 1986; Gage et al, 2005). It has two important biological functions: lens accommodation and production of aqueous and vitreous humor. The aqueous humor nourishes avascular anterior structures and generates the intraocular pressure (IOP), whose elevation is often a risk factor for glaucoma (Stamer and Acott, 2012; Zhang et al, 2012). In spite of the importance of the CB in the mammalian eye, the mechanisms underlying CB development and secretion remain poorly understood
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