Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Molecular Psychiatry (2022)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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.

References

  1. Tong CK, Vidyadaran S. Role of microglia in embryonic neurogenesis. Exp Biol Med. 2016;241:1669–75.

    Article  CAS  Google Scholar 

  2. Schafer DP, Stevens B. Microglia function in central nervous system development and plasticity. Cold Spring Harb Perspect Biol. 2015;7:a020545.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wu Y, Dissing-Olesen L, MacVicar BA, Stevens B. Microglia: dynamic mediators of synapse development and plasticity. Trends Immunol. 2015;36:605–13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Tay TL, Mai D, Dautzenberg J, Fernandez-Klett F, Lin G, Sagar, et al. A new fate mapping system reveals context-dependent random or clonal expansion of microglia. Nat Neurosci. 2017;20:793–803.

    Article  CAS  PubMed  Google Scholar 

  5. Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, et al. Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature. 2015;518:547–51.

    Article  PubMed  CAS  Google Scholar 

  6. Matcovitch-Natan O, Winter DR, Giladi A, Vargas Aguilar S, Spinrad A, Sarrazin S, et al. Microglia development follows a stepwise program to regulate brain homeostasis. Science. 2016;353:aad8670.

    Article  PubMed  CAS  Google Scholar 

  7. Li Q, Cheng Z, Zhou L, Darmanis S, Neff NF, Okamoto J, et al. Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron. 2019;101:207–23.

    Article  CAS  PubMed  Google Scholar 

  8. Hammond TR, Dufort C, Dissing-Olesen L, Giera S, Young A, Wysoker A, et al. Single-cell RNA sequencing of microglia throughout the mouse lifespan and in the injured brain reveals complex cell-state changes. Immunity. 2019;50:253–71.

    Article  CAS  PubMed  Google Scholar 

  9. Masuda T, Sankowski R, Staszewski O, Bottcher C, Amann L, Sagar, et al. Spatial and temporal heterogeneity of mouse and human microglia at single-cell resolution. Nature. 2019;568:E4.

    Article  CAS  PubMed  Google Scholar 

  10. Prinz M, Priller J. Microglia and brain macrophages in the molecular age: from origin to neuropsychiatric disease. Nat Rev Neurosci. 2014;15:300–12.

    Article  CAS  PubMed  Google Scholar 

  11. Hoeffel G, Ginhoux F. Fetal monocytes and the origins of tissue-resident macrophages. Cell Immunol. 2018;330:5–15.

    Article  CAS  PubMed  Google Scholar 

  12. Bruttger J, Karram K, Wortge S, Regen T, Marini F, Hoppmann N, et al. Genetic cell ablation reveals clusters of local self-renewing microglia in the mammalian central nervous system. Immunity. 2015;43:92–106.

    Article  CAS  PubMed  Google Scholar 

  13. Noctor SC, Martinez-Cerdeno V, Ivic L, Kriegstein AR. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat Neurosci. 2004;7:136–44.

    Article  CAS  PubMed  Google Scholar 

  14. Baizabal JM, Mistry M, Garcia MT, Gomez N, Olukoya O, Tran D, et al. The epigenetic state of PRDM16-regulated enhancers in radial glia controls cortical neuron position. Neuron. 2018;99:239–41.

    Article  CAS  PubMed  Google Scholar 

  15. Noctor SC, Flint AC, Weissman TA, Dammerman RS, Kriegstein AR. Neurons derived from radial glial cells establish radial units in neocortex. Nature. 2001;409:714–20.

    Article  CAS  PubMed  Google Scholar 

  16. Squarzoni P, Oller G, Hoeffel G, Pont-Lezica L, Rostaing P, Low D, et al. Microglia modulate wiring of the embryonic forebrain. Cell Rep. 2014;8:1271–9.

    Article  CAS  PubMed  Google Scholar 

  17. Morrison SJ, Spradling AC. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell. 2008;132:598–611.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Deverman BE, Patterson PH. Cytokines and CNS development. Neuron. 2009;64:61–78.

    Article  CAS  PubMed  Google Scholar 

  19. Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science. 2005;308:1314–8.

    Article  CAS  PubMed  Google Scholar 

  20. Zhan Y, Paolicelli RC, Sforazzini F, Weinhard L, Bolasco G, Pagani F, et al. Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. Nat Neurosci. 2014;17:400–6.

    Article  CAS  PubMed  Google Scholar 

  21. Gunner G, Cheadle L, Johnson KM, Ayata P, Badimon A, Mondo E, et al. Sensory lesioning induces microglial synapse elimination via ADAM10 and fractalkine signaling. Nat Neurosci. 2019;22:1075–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ayata P, Badimon A, Strasburger HJ, Duff MK, Montgomery SE, Loh YE, et al. Epigenetic regulation of brain region-specific microglia clearance activity. Nat Neurosci. 2018;21:1049–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kadoch C, Crabtree GR. Mammalian SWI/SNF chromatin remodeling complexes and cancer: mechanistic insights gained from human genomics. Sci Adv. 2015;1:e1500447.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Wu JN, Roberts CWM. ARID1A mutations in cancer: another epigenetic tumor suppressor? Cancer Disco. 2013;3:35–43.

    Article  CAS  Google Scholar 

  25. Bailey MH, Tokheim C, Porta-Pardo E, Sengupta S, Bertrand D, Weerasinghe A, et al. Comprehensive characterization of cancer driver genes and mutations. Cell. 2018;174:1034–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mathur R, Alver BH, San Roman AK, Wilson BG, Wang X, Agoston AT, et al. ARID1A loss impairs enhancer-mediated gene regulation and drives colon cancer in mice. Nat Genet. 2017;49:296–302.

    Article  CAS  PubMed  Google Scholar 

  27. Pulice JL, Kadoch C. Composition and function of mammalian SWI/SNF chromatin remodeling complexes in human disease. Cold Spring Harb Symp Quant Biol. 2016;81:53–60.

    Article  PubMed  Google Scholar 

  28. Sun X, Chuang JC, Kanchwala M, Wu L, Celen C, Li L, et al. Suppression of the SWI/SNF component Arid1a promotes mammalian regeneration. Cell Stem Cell. 2016;18:456–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Li W, Yang L, He Q, Hu C, Zhu L, Ma X, et al. A homeostatic Arid1a-dependent permissive chromatin state licenses hepatocyte responsiveness to liver-injury-associated YAP signaling. Cell Stem Cell. 2019;25:54–68.

    Article  CAS  PubMed  Google Scholar 

  30. Kelso TWR, Porter DK, Amaral ML, Shokhirev MN, Benner C, Hargreaves DC. Chromatin accessibility underlies synthetic lethality of SWI/SNF subunits in ARID1A-mutant cancers. Elife. 2017;6:e30506.

  31. Dekker J, Mirny L. The 3D genome as moderator of chromosomal communication. Cell. 2016;164:1110–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rahmanto YS, Jung JG, Wu RC, Kobayashi Y, Heaphy CM, Meeker AK, et al. Inactivating ARID1A tumor suppressor enhances TERT transcription and maintains telomere length in cancer cells. J Biol Chem. 2016;291:9690–9.

    Article  CAS  PubMed Central  Google Scholar 

  33. Liu JL, Liu S, Gao HY, Han L, Chu XN, Sheng Y, et al. Genome-wide studies reveal the essential and opposite roles of ARID1A in controlling human cardiogenesis and neurogenesis from pluripotent stem cells. Genome Biol. 2020;21:169.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li J, Wang W, Zhang Y, Cieslik M, Guo J, Tan M, et al. Epigenetic driver mutations in ARID1A shape cancer immune phenotype and immunotherapy. J Clin Invest. 2020;130:2712–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA, et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 2003;113:703–16.

    Article  CAS  PubMed  Google Scholar 

  36. Gao X, Tate P, Hu P, Tjian R, Skarnes WC, Wang Z. ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling component BAF250a. Proc Natl Acad Sci USA. 2008;105:6656–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Arno B, Grassivaro F, Rossi C, Bergamaschi A, Castiglioni V, Furlan R, et al. Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex. Nat Commun. 2014;5:5611.

    Article  CAS  PubMed  Google Scholar 

  38. Cunningham CL, Martinez-Cerdeno V, Noctor SC. Microglia regulate the number of neural precursor cells in the developing cerebral cortex. J Neurosci. 2013;33:4216–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kettenmann H, Kirchhoff F, Verkhratsky A. Microglia: new roles for the synaptic stripper. Neuron. 2013;77:10–18.

    Article  CAS  PubMed  Google Scholar 

  40. Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al. Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron. 2012;74:691–705.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kracht L, Borggrewe M, Eskandar S, Brouwer N, Chuva de Sousa Lopes SM, Laman JD, et al. Human fetal microglia acquire homeostatic immune-sensing properties early in development. Science. 2020;369:530–7.

    Article  CAS  PubMed  Google Scholar 

  42. Mathur R, Roberts CWM. SWI/SNF (BAF) complexes: guardians of the epigenome. Annu Rev Cancer Biol. 2018;2:413–27.

    Article  Google Scholar 

  43. Peca J, Feliciano C, Ting JT, Wang WT, Wells MF, Venkatraman TN, et al. Shank3 mutant mice display autistic-like behaviours and striatal dysfunction. Nature. 2011;472:437–U534.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Angoa-Perez M, Kane MJ, Briggs DI, Francescutti DM, Kuhn DM. Marble burying and nestlet shredding as tests of repetitive, compulsive-like behaviors in mice. J Vis Exp. 2013;82:50978.

  45. Ronan JL, Wu W, Crabtree GR. From neural development to cognition: unexpected roles for chromatin. Nat Rev Genet. 2013;14:440.

    Article  CAS  Google Scholar 

  46. Wilson MR, Reske JJ, Holladay J, Neupane S, Ngo J, Cuthrell N, et al. ARID1A mutations promote P300-dependent endometrial invasion through super-enhancer hyperacetylation. Cell Reports. 2020;33:108366.

  47. Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, et al. Synaptic pruning by microglia is necessary for normal brain development. Science. 2011;333:1456–8.

    Article  CAS  PubMed  Google Scholar 

  48. Zechner D, Fujita Y, Hulsken J, Muller T, Walther I, Taketo MM, et al. beta-catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. Dev Biol. 2003;258:406–18.

    Article  CAS  PubMed  Google Scholar 

  49. Tamai K, Zeng X, Liu CM, Zhang XJ, Harada Y, Chang ZJ, et al. A mechanism for Wnt coreceptor activation. Mol Cell. 2004;13:149–56.

    Article  CAS  PubMed  Google Scholar 

  50. MacDonald BT, He X. Frizzled and LRP5/6 receptors for Wnt/beta-catenin signaling. Csh Perspect Biol. 2012;4:a007880.

  51. Bickmore WA, van Steensel B. Genome architecture: domain organization of interphase chromosomes. Cell. 2013;152:1270–84.

    Article  CAS  PubMed  Google Scholar 

  52. Kadoch C, Hargreaves DC, Hodges C, Elias L, Ho L, Ranish J, et al. Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancy. Nat Genet. 2013;45:592–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Dykhuizen EC, Hargreaves DC, Miller EL, Cui K, Korshunov A, Kool M, et al. BAF complexes facilitate decatenation of DNA by topoisomerase IIalpha. Nature. 2013;497:624–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chandler RL, Brennan J, Schisler JC, Serber D, Patterson C, Magnuson T. ARID1a-DNA interactions are required for promoter occupancy by SWI/SNF. Mol Cell Biol. 2013;33:265–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J. Resting microglia directly monitor the functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci. 2009;29:3974–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Aguirre A, Rubio ME, Gallo V. Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal. Nature. 2010;467:323–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Freese JL, Pino D, Pleasure SJ. Wnt signaling in development and disease. Neurobiol Dis. 2010;38:148–53.

    Article  CAS  PubMed  Google Scholar 

  58. Bond AM, Bhalala OG, Kessler JA. The dynamic role of bone morphogenetic proteins in neural stem cell fate and maturation. Dev Neurobiol. 2012;72:1068–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Munji RN, Choe Y, Li G, Siegenthaler JA, Pleasure SJ. Wnt signaling regulates neuronal differentiation of cortical intermediate progenitors. J Neurosci. 2011;31:1676–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Woodhead GJ, Mutch CA, Olson EC, Chenn A. Cell-autonomous beta-catenin signaling regulates cortical precursor proliferation. J Neurosci. 2006;26:12620–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chenn A, Walsh CA. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science. 2002;297:365–9.

    Article  CAS  PubMed  Google Scholar 

  62. Zhang W, Ma L, Yang M, Shao E, Xu J, Lu ZP, et al. Cerebral organoid and mouse models reveal a RAB39b-PI3K-mTOR pathway-dependent dysregulation of cortical development leading to macrocephaly/autism phenotypes. Gene Dev. 2020;34:580–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sadakata T, Washida M, Iwayama Y, Shoji S, Sato Y, Ohkura T, et al. Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients. J Clin Invest. 2007;117:931–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

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).

Author information

Author notes

  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

Authors
  1. Libo Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mengtian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fen Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jinyue Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuanyuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wenwen Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shukui Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hongyan Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yanyan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jianwei Jiao
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding author

Correspondence to Jianwei Jiao.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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 (2022). https://doi.org/10.1038/s41380-022-01703-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41380-022-01703-7

This article is cited by

Search

Advanced search

Quick links