Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, Geert Grooteplein 10, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, 6500 HB, Nijmegen, The Netherlands.
Cell Mol Life Sci. 2021 Mar;78(6):2517-2563. doi: 10.1007/s00018-020-03714-5. Epub 2020 Dec 2.
Neurodevelopmental disorders (NDDs), including intellectual disability (ID) and autism spectrum disorders (ASD), are a large group of disorders in which early insults during brain development result in a wide and heterogeneous spectrum of clinical diagnoses. Mutations in genes coding for chromatin remodelers are overrepresented in NDD cohorts, pointing towards epigenetics as a convergent pathogenic pathway between these disorders. In this review we detail the role of NDD-associated chromatin remodelers during the developmental continuum of progenitor expansion, differentiation, cell-type specification, migration and maturation. We discuss how defects in chromatin remodelling during these early developmental time points compound over time and result in impaired brain circuit establishment. In particular, we focus on their role in the three largest cell populations: glutamatergic neurons, GABAergic neurons, and glia cells. An in-depth understanding of the spatiotemporal role of chromatin remodelers during neurodevelopment can contribute to the identification of molecular targets for treatment strategies.
神经发育障碍（NDD），包括智力障碍（ID）和自闭症谱系障碍（ASD），是一大类疾病，其中大脑发育过程中的早期损伤导致了广泛而不同的临床诊断。编码染色质重塑因子的基因突变在 NDD 队列中过度表达，表明表观遗传学是这些疾病之间的一个集中的致病途径。在这篇综述中，我们详细描述了 NDD 相关染色质重塑因子在祖细胞扩增、分化、细胞类型特化、迁移和成熟的发育连续体中的作用。我们讨论了在这些早期发育时间点染色质重塑缺陷如何随着时间的推移而累积，并导致大脑回路建立受损。特别是，我们关注它们在三种最大的细胞群体中的作用：谷氨酸能神经元、GABA 能神经元和神经胶质细胞。深入了解染色质重塑因子在神经发育过程中的时空作用，可以有助于确定治疗策略的分子靶点。
