The Role of DEAF1 in Dendritic and Synaptic Development: Insights Into Neurodevelopmental Disorders

DEAF1 functions as both a transcriptional activator and repressor and is implicated in neurodevelopmental disorders (NDDs); however, its role in neuronal development remains poorly understood. In this study, we investigated the role of DEAF1 in cortical development, with a particular focus on neuronal architecture, as well as its contributions to synaptic function and neuronal activity. In vitro analyses revealed that dendritic development, but not axonal development, was inhibited in DEAF1-deficient hippocampal neurons. Using in utero electroporation-based acute knockdown experiments, we further demonstrated that DEAF1 knockdown in post-migratory mouse cortical neurons leads to impaired dendritic arborization and reduced dendritic spine density, without significantly affecting neuronal migration or axonal extension. These findings suggest that DEAF1's primary role in neurodevelopment is associated with the later stages of cortical maturation, specifically in dendritic and synaptic development. Additionally, electrophysiological analyses revealed that DEAF1 knockdown reduces both excitatory and inhibitory synaptic transmission. Furthermore, neuronal excitability was significantly reduced, suggesting a potential dysfunction in voltage-gated sodium and/or potassium channels. Collectively, our findings reveal a critical role for DEAF1 in dendritic and synaptic development, providing new insights into the cellular and functional mechanisms underlying DEAF1-associated NDDs.