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Microglia homeostasis mediated by epigenetic ARID1A regulates neural progenitor cells response and leads to autism-like behaviors

Molecular Psychiatry volume 29, pages 1595–1609 (2024)Cite this article

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Abstract

Microglia are resident macrophages of the central nervous system that selectively emerge in embryonic cortical proliferative zones and regulate neurogenesis by altering molecular and phenotypic states. Despite their important roles in inflammatory phagocytosis and neurodegenerative diseases, microglial homeostasis during early brain development has not been fully elucidated. Here, we demonstrate a notable interplay between microglial homeostasis and neural progenitor cell signal transduction during embryonic neurogenesis. ARID1A, an epigenetic subunit of the SWI/SNF chromatin-remodeling complex, disrupts genome-wide H3K9me3 occupancy in microglia and changes the epigenetic chromatin landscape of regulatory elements that influence the switching of microglial states. Perturbation of microglial homeostasis impairs the release of PRG3, which regulates neural progenitor cell self-renewal and differentiation during embryonic development. Furthermore, the loss of microglia-driven PRG3 alters the downstream cascade of the Wnt/β-catenin signaling pathway through its interaction with the neural progenitor receptor LRP6, which leads to misplaced regulation in neuronal development and causes autism-like behaviors at later stages. Thus, during early fetal brain development, microglia progress toward a more homeostatic competent phenotype, which might render neural progenitor cells respond to environmental cross-talk perturbations.

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Fig. 1: Microglia contact specialized areas of neural progenitor cells (NPCs) and ARID1A deletion disrupts the microglial populations.
Fig. 2: Epigenetic ARID1A deletion disrupts microglial homeostasis state during fetal brain development.
Fig. 3: Disruption of microglial homeostasis impairs neural progenitor cells response during embryonic brain development.
Fig. 4: Perturbation of the microglial homeostasis in embryonic period leads to autism-like behaviors.
Fig. 5: The changing chromatin landscape of homeostatic microglia mediates neurogenesis by targeting secretory PRG3 in brain development.
Fig. 6: Homeostatic microglia regulated neurogenesis through the activation of β-catenin signaling in neural progenitor cells.

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Data availability

All sequencing-derived raw RNA data and ChIP-seq datasets reported in this paper are available from GEO (http://www.ncbi.nlm.nih.gov/geo). The accession number for the RNA-seq data is GEO: GSE190926 and the ChIP-seq data is GEO: GSE190450. A detailed description of the computational processing and parameters is provided in “Method” details.

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Acknowledgements

We gratefully thank Lijian Hui and Zhong Wang for providing Arid1afl/fl mice, and we thank Zengqiang Yuan lab for their help in CX3CR1-GFP mice. This work was supported by grants from the National Science Fund for Distinguished Young Scholars (81825006), National Key R&D Program of China (2019YFA0110300), CAS Strategic Priority Research Program (XDA16010301), and the National Natural Science Foundation of China (31730033, 31621004 and 92149304).

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  1. These authors contributed equally: Libo Su, Mengtian Zhang.

Authors and Affiliations

  1. State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China

    Libo Su, Mengtian Zhang, Fen Ji, Jinyue Zhao, Yuanyuan Wang, Wenwen Wang, Shukui Zhang, Hongyan Ma, Yanyan Wang & Jianwei Jiao

  2. University of Chinese Academy of Sciences, 100049, Beijing, China

    Libo Su, Mengtian Zhang, Fen Ji, Jinyue Zhao, Yuanyuan Wang, Hongyan Ma, Yanyan Wang & Jianwei Jiao

  3. Beijing Institute for Stem Cell and Regenerative Medicine, Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, 100101, Beijing, China

    Libo Su, Mengtian Zhang, Fen Ji, Jinyue Zhao, Yuanyuan Wang, Hongyan Ma, Yanyan Wang & Jianwei Jiao

  4. School of Life Sciences, University of Science and Technology of China, Hefei, 230026, China

    Wenwen Wang

  5. College of Life Sciences, Yantai University, Yantai, 264005, Shandong, China

    Shukui Zhang

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Contributions

LS and JJ conceived the experiments. LS performed the experiments and analyzed the data. MZ and FJ provided technical assistance for behavioral tests. JZ and HM performed some of the in utero electroporation. WW and YW performed the identification of mouse genotypes. SZ and YW provided some advices about RNA-seq analysis. LS wrote the manuscript with input from all authors. JJ supervised the project and obtained funding support.

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Correspondence to Jianwei Jiao.

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Su, L., Zhang, M., Ji, F. et al. Microglia homeostasis mediated by epigenetic ARID1A regulates neural progenitor cells response and leads to autism-like behaviors. Mol Psychiatry 29, 1595–1609 (2024). https://doi.org/10.1038/s41380-022-01703-7

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