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Published on: April 13, 2017
Control of microglial dynamics by the Arp2/3 complex and the autism- and schizophrenia-associated protein CYFIP1
James Scott-Solache1, Jiaxin Pei1, James Drew1
1Department of Neuroscience, Physiology and Pharmacology, University College London, London WC1E 6BT, 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.
Insights
Regulators of the actin cytoskeleton, including CYFIP1, control microglial process dynamics. This impacts brain surveillance and lysosome function, potentially influencing neuropsychiatric disease.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Microglia, the brain's immune cells, possess dynamic processes crucial for sensing their environment.
- Microglial motility is implicated in brain development and diseases, yet the underlying intracellular mechanisms remain unclear.
- The actin cytoskeleton plays a role in cell shape and movement, but its specific function in microglial dynamics is not fully understood.
Purpose of the Study:
- To investigate the role of actin cytoskeleton regulators in microglial process dynamics.
- To determine the function of CYFIP1, a neuropsychiatric disease-associated protein, in microglia.
Main Methods:
- Conditional deletion of the Cyfip1 gene in mouse microglia.
- Analysis of microglial morphology, motility (surveillance and chemotaxis), and lysosomal function.
- Assessment of presynaptic engulfment by microglia.
Main Results:
- The Arp2/3 complex is essential for microglial morphology and surveillance motility.
- Conditional deletion of Cyfip1 in microglia reduced morphological complexity and brain surveillance.
- Cyfip1 deletion did not affect chemotactic motility but increased lysosome volume and presynaptic engulfment.
Conclusions:
- Actin remodeling by CYFIP1 and the Arp2/3 complex is critical for microglial surveillance and morphology.
- Loss of CYFIP1 function shifts microglia from a homeostatic state, characterized by increased lysosomal activity and presynaptic engulfment.
- These findings suggest potential implications for understanding and treating neuropsychiatric diseases.
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