Journal
MOLECULAR PSYCHIATRY
Volume -, Issue -, Pages -Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-022-01703-7
Keywords
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Funding
- National Science Fund for Distinguished Young Scholars [81825006]
- National Key R&D Program of China [2019YFA0110300]
- CAS Strategic Priority Research Program [XDA16010301]
- National Natural Science Foundation of China [31730033, 31621004, 92149304]
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Microglial homeostasis and neural progenitor cell signal transduction show a significant interplay during embryonic neurogenesis. ARID1A disrupts the chromatin landscape of microglia, affecting microglial state switching. The perturbation of microglial homeostasis impairs PRG3 release, which impacts neural progenitor cell self-renewal and differentiation during embryonic development. Loss of microglia-driven PRG3 leads to misregulation in the downstream cascade of the Wnt/beta-catenin signaling pathway, resulting in abnormal neuronal development and autism-like behaviors at later stages.
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/beta-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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