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Updated: Aug 5, 2026
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Transcriptional regulation of disease-relevant microglial activation programs
Amanda McQuade1, Reet Mishra2, Venus Hagan1
1Institute for Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA.
Abstract:
Microglia, the brain's innate immune cells, can adopt a wide variety of activation states relevant to health and disease. Dysregulation of microglial activation occurs in numerous brain disorders, and driving or inhibiting specific states could be therapeutic. To discover regulators of microglial activation states, we conducted CRISPR interference screens in induced pluripotent stem cell (iPSC)-derived microglia for inhibitors and activators of six microglial states. We characterized 31 regulators at the single-cell transcriptomic and cell-surface proteome level in two distinct iPSC-derived microglia models, uncovering protein markers of relevant states. We functionally characterized several multi-state regulators. ZNF532 and PRDM1 knockdown drive disease-associated, lipid-rich signatures and enhance phagocytosis while showing opposing effects on antigen-presentation signatures. DNMT1 knockdown results in widespread loss of DNA methylation, activating negative regulators of interferon signaling. These findings provide a framework to direct microglial activation to selectively enrich microglial activation states, define their functional outputs, and inform future therapies.
Insights
Researchers identified key regulators of microglial activation states using CRISPR screens in stem cell-derived microglia. These findings offer a framework for therapeutically directing microglial states in brain disorders.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia, the brain's immune cells, exhibit diverse activation states crucial for neurological health and disease.
- Aberrant microglial activation is implicated in various brain disorders, presenting therapeutic opportunities.
- Targeting specific microglial activation states could offer novel treatment strategies.
Purpose of the Study:
- To identify novel regulators of microglial activation states.
- To discover genetic modifiers that can drive or inhibit specific microglial phenotypes.
- To provide a framework for manipulating microglial states for therapeutic benefit.
Main Methods:
- Utilized CRISPR interference (CRISPRi) screens in induced pluripotent stem cell (iPSC)-derived microglia.
- Assessed inhibitors and activators across six distinct microglial activation states.
- Performed single-cell transcriptomic and cell-surface proteome analysis on identified regulators.
Main Results:
- Identified and characterized 31 regulators of microglial activation.
- Uncovered protein markers associated with specific microglial states.
- Demonstrated that ZNF532 and PRDM1 knockdown induce disease-associated signatures and alter phagocytosis and antigen presentation.
- Showed DNMT1 knockdown leads to DNA hypomethylation and modulates interferon signaling.
Conclusions:
- Established a framework for directing microglial activation states and their functional outcomes.
- Highlighted specific regulators (ZNF532, PRDM1, DNMT1) with potential therapeutic implications.
- Provided insights into the molecular mechanisms governing microglial phenotypes for future neurotherapeutics.
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