DCX knockout ferret disentangles cellular landscape of lissencephaly syndrome and novel functions of DCX in neural progenitors
Lissencephaly (LIS) represents a range of gene-associated brain abnormalities characterized by a smooth cortical surface (due to the absence or reduction of gyri and sulci) in humans. This condition manifests through various symptoms such as seizures, muscle spasms, developmental delays, cognitive impairments, and learning discrepancies, etc.1-3 To date, nearly twenty gene mutations related to lissencephaly have been identified, with DCX and LIS1 being the most commonly reported risk genes in humans1-5. Our understanding of this disease remains limited due to the absence of suitable models that accurately represent human phenotypes. In this study, we conducted a comprehensive examination of the phenotypes, cytoarchitecture, and cellular profiles of the neocortex in DCX knockout ferrets we generated previously 6. Our findings indicate that the DCX knockout ferrets effectively replicate the morphological and pathological phenotypes observed in human patients. Furthermore, we discovered a novel function of DCX in neural progenitor cells (NPCs), that DCX inhibits the proliferation of NPCs and regulates the extension of radial glial fibers, which serve as a migration scaffold for neurons. We also present evidence suggesting that inhibitory neurons pair with their excitatory counterparts in a subtype-specific manner during their migration and distribution in the neocortex, which was also dysregulated in DCX knockout ferrets. Overall design: To investigate the DCX gene function in brain, we established ferret model in which target gene has been knocked down.