Li Yi-Wei, Tu Si-Xin, Li Ze-Xuan, Ding Yu-Qiang, Hu Ling
Laboratory Animal Center, Fudan University, Shanghai 200032, China.
Laboratory Animal Center, Fudan University, Shanghai 200032, China; State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institute of Brain Science, Fudan University, Shanghai 200032, China.
Neurobiol Dis. 2025 Jun 15;210:106913. doi: 10.1016/j.nbd.2025.106913. Epub 2025 Apr 15.
Neurodevelopmental disorders (NDDs) encompass a diverse range of impairments affecting brain development and functions, often presenting as deficits in motor skills, cognitive abilities, language development and neuropsychiatric health. The emergence of next-generation sequencing has unveiled numerous genetic variants linked to NDDs, implicating molecular pathways involved in essential neuronal processes such as synaptic plasticity, neuronal architecture and proteostasis. Central to these processes is the Mediator complex, a highly conserved multi-subunit assembly crucial for RNA polymerase II (Pol II)-dependent transcription. The Mediator functions as a key regulator of gene expression, playing a pivotal role in coordinating cellular processes essential for neuronal differentiation and developmental signaling cascades. Increasingly evidence has shown that its dysfunction is highly associated with the pathogenesis of NDDs. This review aims to comprehensively examine the structural and functional characteristics of individual mediator subunits. We will focus on clinical case reports and recent preclinical studies that highlight the connection between genetic abnormalities in the Mediator complex and specific neurodevelopmental phenotypes, ultimately guiding the development of enhanced diagnostic tools and therapeutic interventions. Furthermore, this review will advance our understanding of the general role transcriptional regulation plays in the etiology of NDDs.
神经发育障碍（NDDs）涵盖了一系列影响大脑发育和功能的不同损伤，通常表现为运动技能、认知能力、语言发育和神经精神健康方面的缺陷。新一代测序技术的出现揭示了许多与NDDs相关的基因变异，涉及到突触可塑性、神经元结构和蛋白质稳态等基本神经元过程中所涉及的分子途径。这些过程的核心是中介体复合物，它是一种高度保守的多亚基组装体，对RNA聚合酶II（Pol II）依赖性转录至关重要。中介体作为基因表达的关键调节因子，在协调神经元分化和发育信号级联所必需的细胞过程中发挥着关键作用。越来越多的证据表明，其功能障碍与NDDs的发病机制高度相关。本综述旨在全面研究单个中介体亚基的结构和功能特征。我们将重点关注临床病例报告和近期的临床前研究，这些研究突出了中介体复合物中的基因异常与特定神经发育表型之间的联系，最终指导改进诊断工具和治疗干预措施的开发。此外，本综述将增进我们对转录调控在NDDs病因学中所起的一般作用的理解。
