神经系统的发育需要精确的调节。调节过程中的任何干扰都可能导致神经发育疾病,比如自闭症和精神分裂症。组蛋白变异是表观遗传调控的重要组成部分。脑发育过程中macroH2A(mH2A)组蛋白变体的功能和机制尚不清楚。这里,我们发现mH2A亚型mH2A1.2的缺失会干扰小鼠的神经干细胞分化。mH2A1.2的缺失影响神经发育,增强神经祖细胞(NPC)增殖,并减少发育中的小鼠大脑中的NPC分化。mH2A1.2缺陷小鼠表现出自闭症样行为,如社会行为和探索能力的缺陷。我们将NKX2.2鉴定为重要的下游效应基因,并表明在mH2A1.2缺失后NKX2.2表达降低,并且NKX2.2的过表达挽救了由mH2A1.2缺失引起的神经元异常。我们的研究表明,mH2A1.2在胚胎神经发生期间减少神经祖细胞的增殖并增强神经元分化,并且这些作用至少部分由NKX2.2介导。这些发现为研究mH2A1.2与神经系统疾病之间的关系提供了基础。
The development of the nervous system requires precise regulation. Any disturbance in the regulation process can lead to neurological developmental diseases, such as autism and schizophrenia. Histone variants are important components of epigenetic regulation. The function and mechanisms of the macroH2A (mH2A) histone variant during brain development are unknown. Here, we show that deletion of the mH2A isoform mH2A1.2 interferes with neural stem cell differentiation in mice. Deletion of mH2A1.2 affects neurodevelopment, enhances neural progenitor cell (NPC) proliferation, and reduces NPC differentiation in the developing mouse brain. mH2A1.2-deficient mice exhibit autism-like behaviors, such as deficits in social behavior and exploratory abilities. We identify
NKX2.2 as an important downstream effector gene and show that
NKX2.2 expression is reduced after mH2A1.2 deletion and that overexpression of
NKX2.2 rescues neuronal abnormalities caused by mH2A1.2 loss. Our study reveals that mH2A1.2 reduces the proliferation of neural progenitors and enhances neuronal differentiation during embryonic neurogenesis and that these effects are at least in part mediated by
NKX2.2. These findings provide a basis for studying the relationship between mH2A1.2 and neurological disorders.