title: Norrin/Frizzled4 signaling in retinal vascular development and blood brain barrier plasticity.
abstract: Norrin/Frizzled4 (Fz4) signaling activates the canonical Wnt pathway to control retinal vascular development. Using genetically engineered mice, we show that precocious Norrin production leads to premature retinal vascular invasion and delayed Norrin production leads to characteristic defects in intraretinal vascular architecture. In genetic mosaics, wild-type endothelial cells (ECs) instruct neighboring Fz4(-/-) ECs to produce an architecturally normal mosaic vasculature, a cell nonautonomous effect. However, over the ensuing weeks, Fz4(-/-) ECs are selectively eliminated from the mosaic vasculature, implying the existence of a quality control program that targets defective ECs. In the adult retina and cerebellum, gain or loss of Norrin/Fz4 signaling results in a cell-autonomous gain or loss, respectively, of blood retina barrier and blood brain barrier function, indicating an ongoing requirement for Frizzled signaling in barrier maintenance and substantial plasticity in mature CNS vascular structure.
authors.affiliation: Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Yanshu
authors.initials: Y
authors.lastname: Wang
authors.forename: Amir
authors.initials: A
authors.lastname: Rattner
authors.forename: Yulian
authors.initials: Y
authors.lastname: Zhou
authors.forename: John
authors.initials: J
authors.lastname: Williams
authors.forename: Philip M
authors.initials: PM
authors.lastname: Smallwood
authors.forename: Jeremy
authors.initials: J
authors.lastname: Nathans
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001813:Blood-Retinal Barrier; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009030:Mosaicism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity; D012160:Retina / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D005136:Eye Proteins; D051157:Frizzled Receptors; C498581:Fzd4 protein, mouse; C489916:Ndph protein, mouse; D009419:Nerve Tissue Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A