Fig. 9: Schematic model of the role of FOXJ3 in cortical development and epilepsy.

A During early cortical development, FOXJ3 is highly expressed in RGCs (blue cells), promoting cell cycle exit and differentiation into deep-layer neurons (layers IV-VI, red and green cells). After E15.5 in mice, FOXJ3 expression declines in RGCs, coinciding with the developmental switch to the generation of upper-layer neurons (layer II/III, yellow cells). Mechanistically, FOXJ3 transcriptionally enhances PTEN expression in progenitor cells, thereby facilitating cell cycle exit, neuronal differentiation, and migration. B In contrast, FOXJ3 dysfunction disrupts this process, resulting in impaired migration and premature production of upper-layer neurons (yellow cells) at the expense of deep-layer neurons (red and green cells). Loss of FOXJ3 reduces PTEN expression in progenitors, leading to hyperactivation of the mTOR pathway and increased phosphorylation of ribosomal protein S6. These changes culminate in delayed cell cycle exit, altered neuronal fate specification, and defective migration (dark green cells). Pathogenic mutations in FOXJ3 are therefore associated with FCD and epilepsy, mediated by impaired regulation of PTEN and consequent dysregulation of the PTEN-mTOR pathway, which also contributes to enlarged neuronal soma resembling dysmorphic neurons in FCD patients. Together, this model highlights FOXJ3 as a key transcription factor orchestrating neuronal specification, laminar organization, and cortical integrity during brain development.