Arhgef1 Deletion Disrupts Early Cortical Neurogenesis via PAK1 Overactivation and Causes Motor Dysfunction in...

Precise regulation of early cortical development is essential for the establishment of normal brain function, and its disruption can contribute to the pathogenesis of neurodevelopmental disorders (NDDs). Impaired motor function is a prominent early manifestation of various NDDs, yet the mechanisms remain elusive. Here, we identified ARHGEF1, a Rho family guanine nucleotide exchange factor highly expressed during early corticogenesis, as a novel regulator in embryonic cortical neurogenesis and adult motor function. By Emx1-Cre-mediated forebrain deletion of Arhgef1 in mice (Arhgef1 cKO mice), early cortical neurogenesis is specifically disrupted, leading to reduced deep-layer cortical neurons. Mechanistically, Arhgef1 deficiency overactivates RAC1/CDC42-PAK1-Cofilin signaling in early cortical development, whereas pharmacological PAK1 inhibition within this critical window rescues the genesis of deep-layer cortical neurons. Importantly, Arhgef1 cKO mice exhibit remarkable motor learning and coordination deficits in adulthood, accompanied by altered neuronal morphology in the motor cortex and impaired neuronal activities in motor circuits. In all, we elucidate a critical developmental window when ARHGEF1 governs corticogenesis via negatively regulates PAK1-dependent pathway and further reveal an important role for ARHGEF1 in maintaining normal motor function in adulthood.