Manifold functions of Mediator complex in neurodevelopmental disorders

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.