Notch Signaling Controls Ciliary Body Morphogenesis and Secretion by Directly Regulating Nectin Protein Expression

Abstract

Anterior segment dysgenesis is often associated with cornea diseases, cataracts and glaucoma. The ciliary body (CB) is a part of the anterior segment that secretes aqueous and vitreous humor that nourishes the eye. Although defective Notch signaling in the CB disrupts CB morphogenesis and causes eye degeneration, the underlying mechanisms remain missing. Here, this study shows that NOTCH signaling controls CB morphogenesis by directly regulating Nectin1 expression, and maintains the vitreous and eye structures by regulating the expression of vitreous proteins and gap junction protein Cx43. Genetic inactivation of Rbpj or both Notch2 and Notch3 in the CB not only disrupts CB morphogenesis but also causes CB epithelial detachment and vitreous shrinkage in the developing eye, and eye degeneration in adults. Molecularly, NOTCH signaling transcriptionally controls the expression of adhesion protein Nectin1 known to be essential for CB morphogenesis, and controls eye pressure and the vitreous through stabilizing gap junction protein Cx43 known to be important for CB secretion. Mechanistically, Nectin1 directly binds and stabilizes Cx43. Finally, NOTCH signaling in the CB also directly controls the expression of vitreous proteins. Therefore, this study has provided important mechanistic insight into how NOTCH signaling controls CB morphogenesis and secretion, and also further suggests the potential involvement of CB secretion in various eye diseases, including retinal degeneration.