Control of microglial dynamics by Arp2/3 and the autism and schizophrenia-associated protein Cyfip1

Abstract

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

Enhanced microglial dynamics and paucity of tau seeding in the amyloid plaque microenvironment contributes to cognitive resilience in Alzheimer’s disease

“…While ARP2 (Actin related protein 2) is part of the Arp2/3 complex, and its role is to engage with actin to start the formation of a new filament branch, CFL1 (Cofilin 1) depolymerizes filaments to make actin available for the formation of new actin structures mediated by CAP1 (Cyclase associated actin cytoskeleton regulatory protein 1) 64 . Considering that a reduction in ARP2 in excitatory synapses has been linked to AD and Down syndrome 65 and that the Arp2/3 complex is critical for maintaining microglial morphology, branching and motility 63,66 , we aimed to determine if ARP2 protein levels are increased in the plaque-AsymAD microenvironment, supporting the spatial transcriptomic data. First, using antibodies against ARP2 (green) and IBA1 (red) we evaluated the levels and distribution of ARP2 in the proximity of amyloid plaques (blue and labeled as P), and in microglia (Fig.…”

Loss of function in the autism and schizophrenia-associated geneCYFIP1in human microglia supports a role in synaptic pruning

“…Loss of CYFIP1 in human iPSC-derived microglia results in altered morphology and motility CYFIP1 is highly expressed in microglia in the human CNS, (10)(11)(12) and the protein has been shown to mediate interactions between the WAVE regulatory complex (WRC) and Arp2/3 complexes (40), allowing the Arp2/3 complex to nucleate the branching and extension of actin filaments (41,42) which in part regulates actin cytoskeleton remodeling during cellular processes involved in morphology and migration that have been implicated in the regulation of murine microglial state. (43) We sought to further characterize potential functional effects by phenotypic comparison of wild type and CYFIP1 loss-of-function clonal iPSC-iMGs including morphology (e.g., resting-state arborization) and motility (e.g., surveillance) that may be related to the activation state, (44) recognizing that microglial activation is not a unidimensional process. That is, we examined phenotypes in CYFIP1 KO iPSC-iMG lines to detect effects on morphology and motility.…”