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.

小胶质细胞是中枢神经系统的常驻巨噬细胞，它们选择性地出现在胚胎皮质增殖区并通过改变分子和表型状态来调节神经发生。尽管它们在炎症性吞噬作用和神经退行性疾病中发挥着重要作用，但早期大脑发育过程中的小胶质细胞稳态尚未完全阐明。在这里，我们展示了胚胎神经发生过程中小胶质细胞稳态和神经祖细胞信号转导之间的显着相互作用。ARID1A 是 SWI/SNF 染色质重塑复合物的表观遗传亚基，可破坏小胶质细胞中全基因组 H3K9me3 的占据，并改变影响小胶质细胞状态转换的调控元件的表观遗传染色质景观。小胶质细胞稳态的扰动会损害 PRG3 的释放，它在胚胎发育过程中调节神经祖细胞的自我更新和分化。此外，小胶质细胞驱动的 PRG3 的缺失通过其与神经祖细胞受体 LRP6 的相互作用改变了 Wnt/β-catenin 信号通路的下游级联反应，从而导致神经元发育的错位调节并导致后期出现自闭症样行为。因此，在胎儿大脑早期发育过程中，小胶质细胞会朝着更具有稳态能力的表型发展，这可能会使神经祖细胞对环境串扰扰动作出反应。小胶质细胞驱动的 PRG3 的缺失通过与神经祖细胞受体 LRP6 的相互作用改变了 Wnt/β-catenin 信号通路的下游级联反应，从而导致神经元发育的错位调节并导致后期出现自闭症样行为。因此，在胎儿大脑早期发育过程中，小胶质细胞会朝着更具有稳态能力的表型发展，这可能会使神经祖细胞对环境串扰扰动作出反应。小胶质细胞驱动的 PRG3 的缺失通过与神经祖细胞受体 LRP6 的相互作用改变了 Wnt/β-catenin 信号通路的下游级联反应，从而导致神经元发育的错位调节并导致后期出现自闭症样行为。因此，在胎儿大脑早期发育过程中，小胶质细胞会朝着更具有稳态能力的表型发展，这可能会使神经祖细胞对环境串扰扰动作出反应。