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Retinal edema typically results from dysfunction of the blood-retina barrier (BRB), which is associated with increased retinal expression of complement components. It is unclear whether the classical complement pathway has detrimental or protective roles in the context of BRB dysfunction. Here, we characterize\n                  <jats:italic>Tspan12<\/jats:italic>\n                  KO\n                  <jats:sup>DBM<\/jats:sup>\n                  (\n                  <jats:underline>D<\/jats:underline>\n                  isrupted\n                  <jats:underline>B<\/jats:underline>\n                  arrier\n                  <jats:underline>M<\/jats:underline>\n                  aintenance) mice, a new mouse model of cystoid edema based on genetically and pharmacologically manipulating beta-catenin-dependent norrin\/frizzled4 (FZD4) signaling. We assess BRB function, cystoid edema, ERG, and microglia activation outcomes in an aging study with WT,\n                  <jats:italic>C1qa<\/jats:italic>\n                  KO,\n                  <jats:italic>Tspan12<\/jats:italic>\n                  KO\n                  <jats:sup>DBM<\/jats:sup>\n                  , and\n                  <jats:italic>Tspan12<\/jats:italic>\n                  KO\n                  <jats:sup>DBM<\/jats:sup>\n                  <jats:italic>; C1qa<\/jats:italic>\n                  KO compound mutant mice. Phenotypic analyses and cell-based experiments indicate that C1QA contributes to maintaining basal beta-catenin-dependent signaling and that the absence of C1QA exacerbates BRB dysfunction, cystoid edema, and neuroinflammation in\n                  <jats:italic>Tspan12<\/jats:italic>\n                  KO\n                  <jats:sup>DBM<\/jats:sup>\n                  <jats:italic>; C1qa<\/jats:italic>\n                  compound mutant mice. Activation of beta-catenin-dependent signaling by a FZD4\/LRP5 agonist antibody modality achieves complete resolution of cystoid edema. This study shows that reducing or enhancing norrin\/frizzled4 signaling can increase or decrease cystoid edema, respectively, underscoring its potential as a therapeutic target in ME. Furthermore, this study provides novel insights into the contribution of C1QA to BRB maintenance.\n                <\/jats:p>","DOI":"10.1101\/2025.07.22.666172","type":"posted-content","created":{"date-parts":[[2025,7,26]],"date-time":"2025-07-26T20:20:12Z","timestamp":1753561212000},"source":"Crossref","is-referenced-by-count":1,"title":["C1q limits cystoid edema by maintaining basal beta-catenin-dependent signaling and blood-retina barrier function"],"prefix":"10.64898","author":[{"given":"Lingling","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacklyn","family":"Levey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md.","family":"Abedin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ha-Neul","family":"Jo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Odame","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaia","family":"Douglas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elise","family":"Thoreen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott W.","family":"McPherson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"Roehrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Somasekar","family":"Seshagiri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephane","family":"Angers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2458-6010","authenticated-orcid":false,"given":"Harald J.","family":"Junge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025072907501112000_2025.07.22.666172v1.1","doi-asserted-by":"crossref","unstructured":"Haydinger CD , Ferreira LB , Williams KA , and Smith JR . 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