title: Ephrin-A3 suppresses Wnt signaling to control retinal stem cell potency.
abstract: The ciliary epithelium (CE) of adult mammals has been reported to provide a source of retinal stem cells (RSCs) that can give rise to all retinal cell types in vitro. A recent study, however, suggests that CE-derived cells possess properties of pigmented ciliary epithelial cells and display little neurogenic potential. Here we show that the neurogenic potential of CE-derived cells is negatively regulated by ephrin-A3, which is upregulated in the CE of postnatal mice and presents a strong prohibitory niche for adult RSCs. Addition of ephrin-A3 inhibits proliferation of CE-derived RSCs and increases pigment 349 cell 359. In contrast, absence of ephrin-A3 promotes proliferation and increases expression of neural progenitor cell markers and photoreceptor progeny. The negative effects of ephrin-A3 on CE-derived RSCs are mediated through activation of an EphA4 receptor and suppression of Wnt3a/β-catenin signaling. Together, our data suggest that CE-derived RSCs contain the intrinsic machinery to generate photoreceptors and other retinal neurons, while the CE of adult mice expresses negative regulators that prohibit the proliferation and neural differentiation of RSCs. Manipulating ephrin and Wnt/β-catenin signaling may, thus, represent a viable approach in activating the endogenous neurogenic potential of CE-derived RSCs for treating photoreceptor damage and retinal degenerative disorders.
authors.affiliation: Department of Ophthalmology and Visual Science, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fang
authors.forename: Kin-Sang
authors.initials: KS
authors.lastname: Cho
authors.forename: Kissaou
authors.initials: K
authors.lastname: Tchedre
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Lee
authors.forename: Chenying
authors.initials: C
authors.lastname: Guo
authors.forename: Hikaru
authors.initials: H
authors.lastname: Kinouchi
authors.forename: Shelley
authors.initials: S
authors.lastname: Fried
authors.forename: Xinghuai
authors.initials: X
authors.lastname: Sun
authors.forename: Dong Feng
authors.initials: DF
authors.lastname: Chen
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D036384:Ephrin-A3 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D018345:Mice, Knockout; D010786:Photoreceptor Cells / Q000166:cytology / Q000378:metabolism; D036122:Receptor, EphA4 / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D060509:Wnt3A Protein / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D036384:Ephrin-A3; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; D036122:Receptor, EphA4