title: Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair.
abstract: Incomplete retinal vascularization occurs in both Norrie disease and familial exudative vitreoretinopathy (FEVR). Norrin, the protein product of the Norrie disease gene, is a secreted protein of unknown biochemical function. One form of FEVR is caused by defects in Frizzled-4 (Fz4), a presumptive Wnt receptor. We show here that Norrin and Fz4 function as a ligand-receptor pair based on (1) the similarity in vascular phenotypes caused by Norrin and Fz4 mutations in humans and mice, (2) the specificity and high affinity of Norrin-Fz4 binding, (3) the high efficiency with which Norrin induces Fz4- and Lrp-dependent activation of the classical Wnt pathway, and (4) the signaling defects displayed by disease-associated variants of Norrin and Fz4. These data define a Norrin-Fz4 signaling system that plays a central role in vascular development in the eye and ear, and they indicate that ligands unrelated to Wnts can act through Fz receptors.
authors.affiliation: Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.forename: Yanshu
authors.initials: Y
authors.lastname: Wang
authors.forename: Alain
authors.initials: A
authors.lastname: Dabdoub
authors.forename: Philip M
authors.initials: PM
authors.lastname: Smallwood
authors.forename: John
authors.initials: J
authors.lastname: Williams
authors.forename: Chad
authors.initials: C
authors.lastname: Woods
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Kelley
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: William
authors.initials: W
authors.lastname: Tasman
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.forename: Jeremy
authors.initials: J
authors.lastname: Nathans
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D002531:Cerebellum / Q000098:blood supply / Q000166:cytology / Q000254:growth & development; D007758:Ear, Inner / Q000098:blood supply* / Q000166:cytology / Q000254:growth & development; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D051157:Frizzled Receptors; D006801:Humans; D026502:LDL-Receptor Related Proteins; D008024:Ligands; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009154:Mutation / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009924:Organ Culture Techniques; D010375:Pedigree; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D012164:Retinal Diseases / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D012171:Retinal Vessels / Q000254:growth & development* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins; D029961:Zebrafish Proteins
chemical_list: D005136:Eye Proteins; C402930:FZD4 protein, human; D051157:Frizzled Receptors; C498581:Fzd4 protein, mouse; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D008024:Ligands; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; C081848:NDP protein, human; C489916:Ndph protein, mouse; D009419:Nerve Tissue Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011973:Receptors, LDL; D051153:Wnt Proteins; D029961:Zebrafish Proteins