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bioRxiv · 10.1101/2025.07.17.664964

The Calcium Pump ATP2B1/PMCA1 Regulates CNS Vascular Development by Facilitating Norrin- and WNT7A/B-induced Frizzled4 signaling

Jo, H.-N.·Kiffmeyer, E.·Zhang, C.·Zhang, L.·Odame, E.·Dinh, Q. C.·Levey, J.·Howe, M.·Roux, K. J.·Fischer, K.-D.·Chen, Z.·Junge, H. J.
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Abstract

Frizzled4 (FZD4) is a receptor for Norrin and WNT7A/B ligands, is expressed in endothelial cells (ECs), is required for endothelial blood-central nervous system (CNS) barrier function as well as CNS angiogenesis, and transduces {beta}-catenin-dependent signaling. 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{superscript 2} Transporting 1 (ATP2B1, also known as PMCA1) as a FZD4 proximity interactor. Functional analyses revealed that ATP2B1 depletion increased EC Ca2+, activated NFAT, and significantly attenuated Norrin/Frizzled4 signaling. Endothelial-specific Atp2b1 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 Ca2+-levels, EC function may be modulated by suppression of {beta}-catenin-dependent signaling.

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Jo, H.-N., Kiffmeyer, E., Zhang, C., Zhang, L., Odame, E., Dinh, Q. C., Levey, J., Howe, M., Roux, K. J., Fischer, K.-D., Chen, Z., Junge, H. J.. 2025-07-22. The Calcium Pump ATP2B1/PMCA1 Regulates CNS Vascular Development by Facilitating Norrin- and WNT7A/B-induced Frizzled4 signaling. https://doi.org/10.1101/2025.07.17.664964

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