The Contribution of Microglial MEF2C to Brain Development

摘要/摘要 智力残疾和自闭症谱系障碍是一种破坏性的障碍，被认为是由 突触功能障碍和神经前体调节改变，目前还没有有效的治疗方法。突变或 心肌细胞增强因子2C(MEF2C)的一个等位基因缺失导致MEF2C单倍体功能不全综合征(MHS)， 精神障碍的特征是表现出严重的智力残疾、重复的运动行为和精神障碍 自闭症谱系上的沟通和社会互动。我们发现MEF2C在人类中高度表达 并发现MEF2C是参与小胶质细胞发育的核心转录因子。 细胞的命运。此外，MEF2C的表达受大脑环境的调节，随着年龄的增长而减少。小胶质细胞 在神经发育障碍的发病机制方面尚未被广泛研究，但有越来越多的证据表明 它们对大脑发育的影响表明它们可能导致儿童的社会和行为缺陷 自闭症。中心假说是小胶质细胞MEF2C在人脑发育过程中起着至关重要的作用 神经发育障碍，包括智力残疾和自闭症的发病机制和由此导致的行为 表型。我们将利用新的体外和体内方法来确定小胶质细胞MEF2C在大脑中的作用 发育包括突触保留和修剪、神经前体细胞池的调节和小胶质细胞 发展。该项目的目标是检验人类小胶质细胞中特定的MEF2C对大脑有贡献的假设 发育和表达减少会导致智力残疾和自闭症患者的神经发育缺陷。 使用表观遗传学技术描述MEF2C转录和环境靶标将产生对 人类小胶质细胞转录网络，并扩展我们对自闭症相关基因的知识，有可能 产生新的治疗靶点。长期目标是利用特定的人类小胶质细胞产生和验证方法 其可用于药物筛选和生成临床前数据，以便最终识别新的潜力 旨在改善自闭症儿童预后的治疗目标。

Summary/Abstract Intellectual disability and autism spectrum disorders are devastating disorders thought to arise from a combination of synaptic dysfunction and altered neural progenitor modulation for which there are no effective treatments. Mutations or deletions in one allele of myocyte enhancer factor 2C (MEF2C) result in MEF2C Haploinsufficiency Syndrome (MHS), a disorder characterized by a severe phenotype with intellectual disability, repetitive motor behaviors, and difficulties with communication and social interaction on the autism spectrum. We have found that MEF2C is highly expressed in human microglia during neurodevelopment and have identified MEF2C as a core transcription factor involved in the microglial cell fate. Furthermore, MEF2C expression is regulated by the brain environment and decreases during aging. Microglia have not been extensively investigated in the pathogenesis of neurodevelopmental disorders, but there is increasing evidence for their impact on brain development suggesting they may contribute to especially the social and behavioral deficits in autism. The central hypothesis is that microglial MEF2C has a crucial role in human brain development and contributes to neurodevelopmental disorders including intellectual disability and autism pathogenesis and the resulting behavioral phenotype. We will utilize novel in vitro and in vivo methods to ascertain the role of microglial MEF2C in brain development including synapse retention and pruning, modulation of the neural progenitor pool, and microglial development. The project goal is to test the hypothesis that MEF2C specifically in human microglia contributes to brain development and reduced expression contributes to neurodevelopmental deficits found in intellectual disability and autism. Delineating MEF2C transcriptional and environmental targets using epigenetic techniques will yield novel insight into human microglial transcriptional networks and expand on our knowledge of autism associated genes with the potential to yield novel therapeutic targets. The long-term goal is to generate and validate methods using human microglia specifically which can be utilized for drug screening and to generate preclinical data in order to ultimately identify novel potential therapeutic targets to improve the outcomes for children with autism.