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bioRxiv · 10.1101/2025.07.22.666172

C1q limits cystoid edema by maintaining basal beta-catenin-dependent signaling and blood-retina barrier function

Zhang, L.·Levey, J.·Abedin, M.·Jo, H.·Odame, E.·Douglas, K.·Thoreen, E.·McPherson, S.·Roehrich, H.·Seshagiri, S.·Angers, S.·Chen, Z.·Junge, H. J.
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Abstract

Macular edema (ME) causes significant vision impairment and occurs in several prevalent retinal diseases including diabetic retinopathy (DR), choroidal neovascularization (CNV), retinal vein occlusion, and uveitis. 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 Tspan12 KODBM (Disrupted Barrier Maintenance) 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, C1qa KO, Tspan12 KODBM, and Tspan12 KODBM; C1qa 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 Tspan12 KODBM; C1qa 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.

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Zhang, L., Levey, J., Abedin, M., Jo, H., Odame, E., Douglas, K., Thoreen, E., McPherson, S., Roehrich, H., Seshagiri, S., Angers, S., Chen, Z., Junge, H. J.. 2025-07-26. C1q limits cystoid edema by maintaining basal beta-catenin-dependent signaling and blood-retina barrier function. https://doi.org/10.1101/2025.07.22.666172

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