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      Molecular determinants in Frizzled, Reck, and Wnt7a for ligand-specific signaling in neurovascular development

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          Abstract

          The molecular basis of Wnt-Frizzled specificity is a central question in developmental biology. Reck, a multi-domain and multi-functional glycosylphosphatidylinositol-anchored protein, specifically enhances beta-catenin signaling by Wnt7a and Wnt7b in cooperation with the 7-transmembrane protein Gpr124. Among amino acids that distinguish Wnt7a and Wnt7b from other Wnts, two clusters are essential for signaling in a Reck- and Gpr124-dependent manner. Both clusters are far from the site of Frizzled binding: one resides at the amino terminus and the second resides in a protruding loop. Within Reck, the fourth of five tandem repeats of an unusual domain with six-cysteines (the CC domain) is essential for Wnt7a stimulation: substitutions P256A and W261A in CC4 eliminate this activity without changing protein abundance or surface localization. Mouse embryos carrying Reck P256A,W261A have severe defects in forebrain angiogenesis, providing the strongest evidence to date that Reck promotes CNS angiogenesis by specifically stimulating Wnt7a and Wnt7b signaling.

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          Most cited references31

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          Norrin/Frizzled4 signaling in retinal vascular development and blood brain barrier plasticity.

          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. Copyright © 2012 Elsevier Inc. All rights reserved.
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            The membrane-anchored MMP inhibitor RECK is a key regulator of extracellular matrix integrity and angiogenesis.

            Matrix metalloproteinases (MMPs) are essential for proper extracellular matrix remodeling. We previously found that a membrane-anchored glycoprotein, RECK, negatively regulates MMP-9 and inhibits tumor invasion and metastasis. Here we show that RECK regulates two other MMPs, MMP-2 and MT1-MMP, known to be involved in cancer progression, that mice lacking a functional RECK gene die around E10.5 with defects in collagen fibrils, the basal lamina, and vascular development, and that this phenotype is partially suppressed by MMP-2 null mutation. Also, vascular sprouting is dramatically suppressed in tumors derived from RECK-expressing fibrosarcoma cells grown in nude mice. These results support a role for RECK in the regulation of MMP-2 in vivo and implicate RECK downregulation in tumor angiogenesis.
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              TSPAN12 regulates retinal vascular development by promoting Norrin- but not Wnt-induced FZD4/beta-catenin signaling.

              Mutations in the genes encoding the Wnt receptor Frizzled-4 (FZD4), coreceptor LRP5, or the ligand Norrin disrupt retinal vascular development and cause ophthalmic diseases. Although Norrin is structurally unrelated to Wnts, it binds FZD4 and activates the canonical Wnt pathway. Here we show that the tetraspanin Tspan12 is expressed in the retinal vasculature, and loss of Tspan12 phenocopies defects seen in Fzd4, Lrp5, and Norrin mutant mice. In addition, Tspan12 genetically interacts with Norrin or Lrp5. Overexpressed TSPAN12 associates with the Norrin-receptor complex and significantly increases Norrin/beta-catenin but not Wnt/beta-catenin signaling, whereas Tspan12 siRNA abolishes transcriptional responses to Norrin but not Wnt3A in retinal endothelial cells. Signaling defects caused by Norrin or FZD4 mutations that are predicted to impair receptor multimerization are rescued by overexpression of TSPAN12. Our data indicate that Norrin multimers and TSPAN12 cooperatively promote multimerization of FZD4 and its associated proteins to elicit physiological levels of signaling.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                21 June 2019
                2019
                : 8
                : e47300
                Affiliations
                [1 ]deptDepartment of Molecular Biology and Genetics Johns Hopkins University School of Medicine BaltimoreUnited States
                [2 ]Howard Hughes Medical Institute, Johns Hopkins University School of Medicine BaltimoreUnited States
                [3 ]deptDepartment of Neuroscience Johns Hopkins University School of Medicine BaltimoreUnited States
                [4 ]deptDepartment of Ophthalmology Johns Hopkins University School of Medicine BaltimoreUnited States
                University of California, San Diego United States
                Max Planck Institute for Heart and Lung Research Germany
                University of California, San Diego United States
                University of California, San Diego United States
                UC Davis School of Medicine United States
                University Hospital Frankfurt Germany
                Author information
                https://orcid.org/0000-0002-0929-6536
                https://orcid.org/0000-0001-8106-5460
                Article
                47300
                10.7554/eLife.47300
                6588345
                31225798
                ed69ef70-fdb5-4583-b404-86ffd9ac9a27
                © 2019, Cho et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 01 April 2019
                : 07 June 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000053, National Eye Institute;
                Award ID: R01EY018637
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000997, Arnold and Mabel Beckman Foundation;
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Short Report
                Developmental Biology
                Neuroscience
                Custom metadata
                Molecular dissection of Frizzled, Reck, and Wnt7a provides critical insight into the long-standing question of ligand-receptor specificity in the field of Wnt signaling.

                Life sciences
                canonical wnt signaling,gpr124,reck,wnt7,blood-brain barrier,cns angiogenesis,mouse
                Life sciences
                canonical wnt signaling, gpr124, reck, wnt7, blood-brain barrier, cns angiogenesis, mouse

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