FOXJ3 REGULATES CORTICAL NEUROGENESIS AND LAMINATION VIA THE PTEN-MTOR SIGNALING PATHWAY

Focal cortical dysplasia (FCD) is a leading cause of drug-resistant epilepsy, characterized by disrupted neuronal migration and abnormal cortical lamination. However, the precise transcriptional mechanisms governing these developmental defects remain incompletely understood. This study investigated the role of the transcription factor Forkhead Box J3 (FOXJ3) in regulating cortical neurogenesis. By combining patient genetic analysis, in utero electroporation-mediated gene manipulation in mice, and molecular profiling including ChIP-seq and scRNA-seq, we examined the impact of FOXJ3 deficiency. We found that FOXJ3 expression normally declines in neural progenitors after mid-gestation. Its knockdown resulted in aberrant neural progenitor proliferation, arrested radial migration, and abnormal neuronal differentiation, ultimately leading to disorganized cortical lamination. Mechanistically, transcriptomic and chromatin analyses identified Pten as a direct downstream target of FOXJ3. Rescue experiments demonstrated that Pten overexpression robustly ameliorated migration defects and corrected laminar abnormalities. In contrast, overexpression of Tsc1 restored progenitor proliferation but failed to fully rescue laminar organization. Furthermore, clinically identified FCD-associated FOXJ3 variants failed to activate Pten transcription, resulting in dysregulated mTOR signaling and neuronal hypertrophy. These findings define a critical FOXJ3-PTEN-mTOR transcriptional program regulating cortical development and highlight FOXJ3 dysfunction as a key molecular contributor to FCD pathogenesis.