Vascular Development in the Retina and Inner Ear
Open accessAbstract
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.
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Norrin and R-Spondin2 can bind to the LRP5/6 receptor and may activate Wnt signaling independent of a Wnt ligand.
“An interesting recent finding is the identification of factors including Norrin23 and R-Spondin2,24 which can bind to the LRP5/6 receptor and may activate Wnt signaling independent of a Wnt ligand.”
From Wnt signal transduction pathways (2008) · cites this paper as [23]
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- Authors
- Xu, Q., Wang, Y., Dabdoub, A., Smallwood, P. M., Williams, J., Woods, C., Kelley, M. W., Jiang, L., Tasman, W., Zhang, K., & Nathans, J.
- Affiliations
- Howard Hughes Medical Institute (US)
- National Institutes of Health (US)
- University of Utah (US)
- Wills Eye Hospital (US)
- Corresponding author
- Nathans, Jeremy
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2004-03
- Volume
- 116
- Issue
- 6
- Pages
- 883-895
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2031522329
- Cited by
- 875
- References
- 41
- Citations by year
- 2026: 26 · 2025: 32 · 2024: 36 · 2023: 38 · 2022: 58 · 2021: 39 · 2020: 34 · 2019: 46 · 2018: 38 · 2017: 47 · 2016: 33 · 2015: 33 · 2014: 43 · 2013: 27 · 2012: 50
- FWCI
- 14.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Ocular Disorders and Treatments
- Keywords
- Norrin, Norrie disease, familial exudative vitreoretinopathy, Frizzled-4, Wnt signaling, ligand-receptor pairs, retinal vascular development, inner ear development, LRP, disease-associated variants
- MeSH terms
- Animals, Binding Sites, Cells, Cultured, Cerebellum, Eye Proteins, Female, Humans, Ear, Inner, Ligands, Male, Microscopy, Electron, Mutation, Neovascularization, Pathologic, Nerve Tissue Proteins, Organ Culture Techniques, Pedigree, Proteins, Proto-Oncogene Proteins, Receptors, Cell Surface, Receptors, LDL, Retinal Diseases, Retinal Vessels, Signal Transduction, Mice, Knockout, LDL-Receptor Related Proteins, Zebrafish Proteins, Receptors, G-Protein-Coupled, Wnt Proteins, Frizzled Receptors, Mice, Low Density Lipoprotein Receptor-Related Protein-5
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