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Despite its fundamental importance in neurovascular biology, including as a drug target, the molecular mechanisms governing FZD4 regulation remain poorly understood. Here, we employed proximity biotinylation to identify proteins that regulate FZD4. We identified ATPase Plasma Membrane Ca\u00b2\u207a Transporting 1 (ATP2B1, also known as PMCA1) as a FZD4 proximity interactor. Functional analyses revealed that ATP2B1 depletion increased EC Ca\n                  <jats:sup>2+<\/jats:sup>\n                  , activated NFAT, and significantly attenuated Norrin\/Frizzled4 signaling. Endothelial-specific\n                  <jats:italic>Atp2b1<\/jats:italic>\n                  deletion caused CNS vascular phenotypes consistent with compromised Norrin\/Frizzled4 signaling. This study identifies ATP2B1 as a novel regulator of Norrin- and WNT7A\/B-induced FZD4 signaling and suggests that in pathological contexts with elevated EC Ca\n                  <jats:sup>2+<\/jats:sup>\n                  -levels, EC function may be modulated by suppression of \u03b2-catenin-dependent signaling.\n                <\/jats:p>","DOI":"10.1101\/2025.07.17.664964","type":"posted-content","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T18:35:13Z","timestamp":1753209313000},"source":"Crossref","is-referenced-by-count":0,"title":["The Calcium Pump ATP2B1\/PMCA1 Regulates CNS Vascular Development by Facilitating Norrin- and WNT7A\/B-induced Frizzled4 Signaling"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2602-5754","authenticated-orcid":false,"given":"Ha-Neul","family":"Jo","sequence":"first","affiliation":[{"name":"University of Minnesota, Graduate Program in Molecular, Cellular, Developmental Biology, and Genetics, Minneapolis, MN"},{"name":"University of Minnesota, Department of Ophthalmology and Visual Neurosciences, Minneapolis, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Kiffmeyer","sequence":"additional","affiliation":[{"name":"University of Minnesota, Department of Neuroscience, Minneapolis, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY"},{"name":"Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingling","family":"Zhang","sequence":"additional","affiliation":[{"name":"University of Minnesota, Department of Ophthalmology and Visual Neurosciences, Minneapolis, MN"},{"name":"University of St. Thomas, Department of Biology, Saint Paul, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emmanuel","family":"Odame","sequence":"additional","affiliation":[{"name":"University of Minnesota, Graduate Program in Molecular, Cellular, Developmental Biology, and Genetics, Minneapolis, MN"},{"name":"University of Minnesota, Department of Ophthalmology and Visual Neurosciences, Minneapolis, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Quynh Chau","family":"Dinh","sequence":"additional","affiliation":[{"name":"University of Minnesota, Department of Ophthalmology and Visual Neurosciences, Minneapolis, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacklyn","family":"Levey","sequence":"additional","affiliation":[{"name":"University of Minnesota, Graduate Program in Molecular, Cellular, Developmental Biology, and Genetics, Minneapolis, MN"},{"name":"University of Minnesota, Department of Ophthalmology and Visual Neurosciences, Minneapolis, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miranda","family":"Howe","sequence":"additional","affiliation":[{"name":"University of Minnesota, Graduate Program in Molecular, Cellular, Developmental Biology, and Genetics, Minneapolis, MN"},{"name":"University of Minnesota, Department of Ophthalmology and Visual Neurosciences, Minneapolis, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle J.","family":"Roux","sequence":"additional","affiliation":[{"name":"Enabling Technology Group, Sanford Research, Sioux Falls, SD"},{"name":"Department of Pediatrics, Sanford School of Medicine, University of South Dakota, Sioux Falls, SD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaus-Dieter","family":"Fischer","sequence":"additional","affiliation":[{"name":"Institute for Biochemistry and Cell Biology, Otto-von-Guericke University, Medical Faculty, Magdeburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe","family":"Chen","sequence":"additional","affiliation":[{"name":"University of Minnesota, Department of Neuroscience, Minneapolis, MN"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Harald J.","family":"Junge","sequence":"additional","affiliation":[{"name":"University of Minnesota, Graduate Program in Molecular, Cellular, Developmental Biology, and Genetics, Minneapolis, MN"},{"name":"University of Minnesota, Department of Ophthalmology and Visual Neurosciences, Minneapolis, 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