NOTCH Signaling Controls Ciliary Body Morphogenesis and Secretion by Directly Regulating Nectin Protein Expression
Ji Pang,
Liang Le,
Yi Zhou,
Renjun Tu,
Qiang Hou,
Dai Tsuchiya,
Nancy Thomas,
Yongfu Wang,
Zulin Yu,
Richard Alexander,
Marina Thexton,
Brandy Lewis,
Timothy Corbin,
Michael Durnin,
Hua Li,
Ruth Ashery-Padan,
Deyue Yan,
Ting Xie
Affiliations
Ji Pang
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA; School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
Liang Le
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA
Yi Zhou
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA; Department of Anatomy and Cell Biology, University of Kansas School of Medicine, 3901 Rainbow Blvd, Kansas City, KS 66160, USA
Renjun Tu
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA
Qiang Hou
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA; State Key Laboratory and Key Laboratory of Vision Science, School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
Dai Tsuchiya
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA
Nancy Thomas
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA
Yongfu Wang
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA
Zulin Yu
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA
Richard Alexander
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA
Marina Thexton
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA
Brandy Lewis
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA
Timothy Corbin
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA
Michael Durnin
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA
Hua Li
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA
Ruth Ashery-Padan
Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Deyue Yan
School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China
Ting Xie
Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA; Department of Anatomy and Cell Biology, University of Kansas School of Medicine, 3901 Rainbow Blvd, Kansas City, KS 66160, USA; Corresponding author
Summary: 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.
