Wnt/β-catenin signaling directs animal development and tissue renewal in a tightly controlled, cell- and tissue-specific manner. In the mammalian central nervous system, the atypical ligand Norrin controls angiogenesis and maintenance of the blood-brain barrier and blood-retina barrier through the Wnt/β-catenin pathway. Like Wnt, Norrin activates signaling by binding and heterodimerizing the receptors Frizzled (Fzd) and low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6), leading to membrane recruitment of the intracellular transducer Dishevelled (Dvl) and ultimately stabilizing the transcriptional coactivator β-catenin. Unlike Wnt, the cystine knot ligand Norrin only signals through Fzd4 and additionally requires the co-receptor Tetraspanin12 (Tspan12); however, the mechanism underlying Tspan12-mediated signal enhancement is unclear. It has been proposed that Tspan12 integrates into the Norrin-Fzd4 complex to enhance Norrin-Fzd4 affinity or otherwise allosterically modulate Fzd4 signaling. Here, we measure direct, high-affinity binding between purified Norrin and Tspan12 in a lipid environment and use AlphaFold models to interrogate this interaction interface. We find that Tspan12 and Fzd4 can simultaneously bind Norrin and that a pre-formed Tspan12/Fzd4 heterodimer, as well as cells co-expressing Tspan12 and Fzd4, more efficiently capture low concentrations of Norrin than Fzd4 alone. We also show that Tspan12 competes with both heparan sulfate proteoglycans and LRP6 for Norrin binding and that Tspan12 does not impact Fzd4-Dvl affinity in the presence or absence of Norrin. Our findings suggest that Tspan12 does not allosterically enhance Fzd4 binding to Norrin or Dvl, but instead functions to directly capture Norrin upstream of signaling.
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http://dx.doi.org/10.7554/eLife.96743 | DOI Listing |
Elife
January 2025
Departments of Molecular & Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, United States.
Wnt/β-catenin signaling directs animal development and tissue renewal in a tightly controlled, cell- and tissue-specific manner. In the mammalian central nervous system, the atypical ligand Norrin controls angiogenesis and maintenance of the blood-brain barrier and blood-retina barrier through the Wnt/β-catenin pathway. Like Wnt, Norrin activates signaling by binding and heterodimerizing the receptors Frizzled (Fzd) and low-density lipoprotein receptor-related protein 5 or 6 (LRP5/6), leading to membrane recruitment of the intracellular transducer Dishevelled (Dvl) and ultimately stabilizing the transcriptional coactivator β-catenin.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
December 2024
Paris Cardiovascular Research Center, Université Paris Cité, Inserm U970, Paris F-75015, France.
The integrity of the blood-retina barrier (BRB) is crucial for phototransduction and vision, by tightly restricting transport of molecules between the blood and surrounding neuronal cells. Breakdown of the BRB leads to the development of retinal diseases. Here, we show that Netrin-1/Unc5b and Norrin/Lrp5 signaling establish a zonated endothelial cell gene expression program that controls BRB integrity.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
December 2024
Developmental Biology and Cancer Department, University College London Great Ormond Street Institute of Child Health, University College London, and National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, London WC1N 1EH, United Kingdom.
Variants in the gene cause Norrie disease, a severe dual-sensory disorder characterized by congenital blindness due to disrupted retinal vascular development and progressive hearing loss accompanied by sensory hair cell death. encodes the secreted signaling molecule norrin. The role of norrin in the cochlea is incompletely understood.
View Article and Find Full Text PDFOphthalmol Retina
August 2024
Department of Ophthalmology, University of Occupational and Environmental Health, Kitakyushu, Japan. Electronic address:
Purpose: To determine the ultra-widefield fluorescein angiographic (UWFA) characteristics of patients with mild familial exudative vitreoretinopathy (FEVR) who had been confirmed to have pathogenic variants of the autosomal dominant (AD) genes of FEVR.
Design: Single center, observational case series.
Subjects And Controls: Thirty-seven patients with mild FEVR from 27 families who had pathogenic variants of the Norrin/β-catenin genes were studied.
J Vitreoretin Dis
April 2024
Retina Consultants, Ltd, Des Plaines, IL, USA.
To describe a patient with familial exudative vitreoretinopathy (FEVR) and the treatment course. A case was evaluated. A 3-year-old boy presented with severe onset of FEVR, with a subhyaloid hemorrhage in 1 eye and tractional retinal detachment (TRD) in the fellow eye.
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