By Jennifer Sokolowski, MD, PhD.
Microglia play a critical role in pruning neurons and synapses during homeostatic maintenance in the adult brain.1 A study by Ayata et al. (2018) identified regional differences in clearance and found a role for epigenetic control via polycomb repressive complex 2 (PRC2) in adult rodents.2
Evaluating microglial clearance
Ayata et al. defined a cell clearance phenotype by labeling microglia with iba1 and CD68 and evaluating morphology, cell volume, and CD68+ lysosome content. They also quantified nuclear fragments (using DAPI staining) within microglial lysosomes as an indicator of clearance.
How is microglial clearance regulated?
Interestingly, Ayata et al. found region-specific differences in cell clearance phenotype. Specifically, cerebellar microglia displayed higher clearance activity than striatal or cortical microglia. Cerebellar microglia had higher expression of genes associated with cell clearance functions; for example, they showed increased MMR (mannose Receptor C-Type 1), AXL (TAM receptor tyrosine kinases ), and LC3 (Microtubule-associated proteins 1A/1B light chain 3B) in cerebellar microglia compared to striatal microglia.
They observed higher neuronal turnover in the cerebellum and hypothesized this mediated the different microglial phenotype. In support of this, they showed that exposing forebrain microglia to apoptotic cells evoked the gene expression patterns associated with clearance activity.
Ultimately, they showed polycomb repressive complex 2 (PRC2) plays a critical role through epigenetically restricting expression of genes supporting clearance activity. Loss of PRC2 activity switched microglia toward the clearance phenotype. Notably, modifying clearance activity through disruption of PRC2 activity had measurable downstream effects on behavior.
| Polycomb repressive complex 2 members: Gene silencing is mediated via H3K27Me2/3 | |
|---|---|
| EZH2 SUZ12 EED RbAp48 |
Core components required for enzymatic activity5 |
| JARID2 | Regulates PCR2 enzymatic activity |
| PHF1 | Regulates PCR2 enzymatic activity and targeting |
| AEBP2 | Zinc finger protein that enhances PCR2 enzymatic activity |
Significance
Studies have shown that defects in microglial pruning lead to changes in network activity that have functional implications.3 Ultimately, it is likely that defects in homeostatic clearance play a role in many neurological diseases.4
Jennifer Sokolowski, MD, PhD
University of Virginia, Department of Neurosurgery
Jennifer is doing a postdoc while completing her residency in Neurosurgery and has background in basic science, specifically neuroscience, cell death, and immunology, as well as background in medicine and translational and clinical research.
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Barger, N. et al. (2018) Microglia: An Intrinsic Component of the Proliferative Zones in the Fetal Rhesus Monkey (Macaca mulatta) Cerebral Cortex Cereb Cortex
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Ayata, P. et al. (2018) Epigenetic regulation of brain region-specific microglia clearance activity Nat Neurosci 21:1049-1060.
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Hong, S. et al. (2016) New insights on the role of microglia in synaptic pruning in health and disease Curr Opin Neurobiol 36:128-134.
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Clayton, K.A. et al. (2017) Alzheimer's Disease: The Role of Microglia in Brain Homeostasis and Proteopathy Front Neurosci
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Margueron R. & Reinberg D. (2011) The Polycomb complex PRC2 and its mark in life. Nature. 469:343. PMID: 21248841.