Control of microglial dynamics by the Arp2/3 complex and the autism- and schizophrenia-associated protein CYFIP1.

Overview

1. Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, United Kingdom
2. Maastricht Centre for Systems Biology and Bioinformatics, Faculty of Science and Engineering, Maastricht University, Maastricht 6229 EN, Netherlands
3. United Kingdom Dementia Research Institute at University College London, Institute of Neurology, Faculty of Brain Sciences, University College London, London WC1E 6BT, United Kingdom
4. The Cellular Phase of Alzheimer’s Disease Laboratory, The Francis Crick Institute, London NW1 1AT, United Kingdom

Abstract

Microglia use a highly complex and dynamic network of branched processes to sense and respond to their surroundings. Despite emerging evidence that microglial motility plays important roles in brain development, neurodegeneration, and neuropsychiatric disease, little is known about the intracellular machinery orchestrating microglial process dynamics. Here, we identify roles for regulators of the actin cytoskeleton in controlling microglial behavior. We show that the actin branching Arp2/3 complex is critical for maintaining microglial morphology and is required for surveillance but not chemotactic motility. Neuropsychiatric disease-associated CYFIP1, a core component of the WAVE regulatory complex linking upstream signaling pathways to activation of the Arp2/3 complex, is highly expressed in microglia but has an unknown function. We report that conditional deletion of Cyfip1 in mouse microglia reduces their morphological complexity and surveillance of the brain parenchyma, with no effect on chemotaxis. Deletion of Cyfip1 also increased microglial CD68 positive lysosome volume and engulfment of presynapses. Thus, actin remodeling by CYFIP1 and the Arp2/3 complex controls microglial dynamics and shifts microglia away from a homeostatic state with potential implications for neuropsychiatric disease.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 5 keywords, 13 MeSH terms, 1 funder, 88 references.

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Scott-Solache, J., Pei, J., Drew, J., López-Doménech, G., Jolivet, R. B., Nieto-Rostro, M., Davenport, E. C., Arancibia-Cárcamo, I. L., Attwell, D., & Kittler, J. T. (2026). Control of microglial dynamics by the Arp2/3 complex and the autism- and schizophrenia-associated protein CYFIP1. Proceedings of the National Academy of Sciences of the United States of America, 123(11), e2532488123. https://doi.org/10.1073/pnas.2532488123

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