Control of microglial dynamics by Arp2/3 and the autism and schizophrenia-associated protein Cyfip1
Open accessAbstract
Microglia use a highly complex and dynamic network of processes to sense and respond to their surroundings. Microglial dynamics differ throughout development and in neurological and neuropsychiatric disease, though mechanistic insight into these changes is lacking. Here we identify novel roles for regulators of the actin cytoskeleton in controlling microglial behaviour. We show that the actin branching complex Arp2/3 is critical for maintaining microglial morphology and required for surveillance but not chemotactic motility. Neuropsychiatric disease-associated Cyfip1, a core component of the WAVE regulatory complex that links Rac1 signalling to Arp2/3 activation, is highly expressed in microglia but has unknown function. We report that conditional deletion of Cyfip1 in mouse microglia reduces morphological complexity and surveillance of brain parenchyma, and increases activation state as defined by CD68 expression. Thus, altered actin-dependent microglial dynamics mediated by Cyfip1 and Arp2/3 may contribute to neuropsychiatric disease.
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The literature highlights the crucial involvement of ACTR2 and CFL1 in microglial motility.
“the literature also highlights their crucial involvement in microglial motility [18, 20].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [20]
In ‘Inhibition of Arp2/3 and Rac1 leads to defects in surveillance of brain parenchyma’ (page unavailable), Arp2/3 inhibition reduced microglial surveillance by over 50%, supporting the motility point for the Arp2/3 complex. The paper does not establish a specific role for ACTR2 separately or address CFL1/cofilin; it also reports that chemotaxis was unaffected by Arp2/3 inhibition. (LLM, conf=0.86)
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References 86 · Cited by 12
Research works printed but not linked: 3
- Bennett, M.L., Bennett, F.C., Liddelow, S.A., Ajami, B., Zamanian, J.L., Fernhoff, N.B., Mulinyawe, S.B., Bohlen, C.J., Adil, A., Tucker, A., et al. (2016). New tools for studying microglia in the mouse and human CNS. Proc. Natl. Acad. Sci. USA 113, E1738-46.
- Koronakis, V., Hume, P.J., Humphreys, D., Liu, T., Hørning, O., Jensen, O.N., and McGhie, E.J. (2011). WAVE regulatory complex activation by cooperating GTPases Arf and Rac1. Proc. Natl. Acad. Sci. USA 108, 14449-14454.
- Madry, C., Arancibia-Cárcamo, I.L., Kyrargyri, V., Chan, V.T.T., Hamilton, N.B., and Attwell, D. (2018a). Effects of the ecto-ATPase apyrase on microglial ramification and surveillance reflect cell depolarization, not ATP depletion. Proc. Natl. Acad. Sci. USA 115, E1608-E1617.
- Authors
- Drew, J., Arancibia-Carcamo, I. L., Jolivet, R., Lopez-Domenech, G., Attwell, D., & Kittler, J. T.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- University of Geneva (CH)
- University College London (GB)
- Corresponding author
- Kittler, Josef T.
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2020-06-01
- OpenAlex
- W3031738640
- Cited by
- 12
- References
- 86
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 3 · 2023: 2 · 2022: 1 · 2021: 1 · 2018: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- Wellcome Trust (219366, 099222)
- Medical Research Council (MR/N025644/1, G0802377)
- FP7 Ideas: European Research Council (282430)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- microglia, Arp2/3 complex, CYFIP1, actin cytoskeleton, microglial morphology, microglial surveillance, microglial activation, CD68, WAVE regulatory complex, autism spectrum disorder, schizophrenia, neuropsychiatric disorders, conditional gene deletion
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