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Updated: Sep 4, 2025
Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Abnormal microglial polarization induced by Arid1a deletion leads to neuronal differentiation deficits
Maolei Gong1,2,3, Ruoxi Shi1,2,3,4, Yijun Liu1,2,3,4
1State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Objective:
Microglia, the prototypical innate immune cells of the central nervous system (CNS), are highly plastic and assume their phenotypes dependent on intrinsically genetic, epigenetic regulation or extrinsically microenvironmental cues. Microglia has been recognized as key regulators of neural stem/progenitor cells (NSPCs) and brain functions. Chromatin accessibility is implicated in immune cell development and functional regulation. However, it is still unknown whether and how chromatin remodelling regulates the phenotypic plasticity of microglia and exerts what kind of effects on NSPCs.
Methods:
We investigated the role of chromatin accessibility in microglia by deleting chromatin remodelling gene Arid1a using microglia-specific Cx3cr1-cre and Cx3cr1-CreERT2 mice. RNA-seq and ATAC-seq were performed to dissect the molecular mechanisms. In addition, we examined postnatal M1/M2 microglia polarization and analysed neuronal differentiation of NSPCs. Finally, we tested the effects of microglial Arid1a deletion on mouse behaviours.
Results:
Increased chromatin accessibility upon Arid1a ablation resulted in enhanced M1 microglial polarization and weakened M2 polarization, which led to abnormal neurogenesis and anxiety-like behaviours. Switching the polarization state under IL4 stimulation could rescue abnormal neurogenesis, supporting an essential role for chromatin remodeler ARID1A in balancing microglial polarization and brain functions.
Conclusions:
Our study identifies ARID1A as a central regulator of microglia polarization, establishing a mechanistic link between chromatin remodelling, neurogenesis and mouse behaviours, and highlights the potential development of innovative therapeutics exploiting the innate regenerative capacity of the nervous system.
Insights
Chromatin remodeler ARID1A regulates microglial polarization, impacting neurogenesis and behavior. Restoring microglial balance offers therapeutic potential for nervous system disorders.
Area of Science:
- Neuroimmunology
- Epigenetics
- Neuroscience
Background:
- Microglia, the CNS's innate immune cells, exhibit plasticity influenced by genetic and environmental factors.
- Microglia regulate neural stem/progenitor cells (NSPCs) and overall brain function.
- Chromatin accessibility is crucial for immune cell function, but its role in microglial plasticity and NSPC regulation remains unclear.
Purpose of the Study:
- To investigate the role of chromatin remodeling, specifically the gene Arid1a, in regulating microglial phenotypic plasticity.
- To determine the effects of altered chromatin accessibility in microglia on neural stem/progenitor cells and brain function.
- To explore the potential therapeutic implications of targeting microglial chromatin remodeling.
Main Methods:
- Deletion of the chromatin remodeling gene Arid1a in microglia using specific mouse models (Cx3cr1-cre and Cx3cr1-CreERT2).
- RNA-sequencing (RNA-seq) and ATAC-sequencing (ATAC-seq) to analyze molecular mechanisms.
- Assessment of M1/M2 microglial polarization, NSPC neuronal differentiation, and mouse behaviors.
Main Results:
- Arid1a ablation increased chromatin accessibility, leading to enhanced M1 and weakened M2 microglial polarization.
- Abnormal neurogenesis and anxiety-like behaviors were observed following Arid1a deletion.
- Restoring microglial polarization with IL4 stimulation rescued neurogenesis deficits.
Conclusions:
- ARID1A is identified as a key regulator of microglial polarization.
- A mechanistic link is established between chromatin remodeling, microglial function, neurogenesis, and behavior.
- Targeting ARID1A presents potential for novel therapeutics leveraging the nervous system's regenerative capacity.
