Epilepsy-Associated FOXJ3 Variants Link a Transcriptional Program of the PTEN-mTOR Pathway to Neuronal Specification and Cortical Lamination Cheng HY, Liu C, Nien CW, Huang HC, Zhao HJ, Nian FS, Chen C, Custodio HM, Sisodiya SM, Lu C, Chen HH, Hsu CS, Pi WC, Chu CC, Hsu JS, Chen PL, Chang FP, Tung CY, Chou SJ, Alavi S, Houlden H, Chen WY, Liu YT, Hou PS, Tsai JW. Nat Commun . 2026;17(1):1815. doi: 10.1038/s41467-026-69241-2. PMID: 41803108; PMCID: PMC12972129. Focal cortical dysplasia (FCD), a major cause of drug-resistant epilepsy, involves abnormal neuronal migration and cortical architecture, yet its molecular basis remains poorly defined. Here, we identify FOXJ3 pathogenic variants in patients with autosomal dominant focal epilepsy and FCD. In the developing mouse cortex, FOXJ3 declines sharply in neural progenitors after embryonic day 15.5. In utero electroporation-mediated Foxj3 knockdown in mouse brains impairs neuronal migration, disrupts cortical lamination, and alters neuronal specification, promoting upper-layer neuron production at the expense of deeper-layer neurons. ChIP-seq and scRNA-seq analyses identify Pten as a key FOXJ3 target. Notably, Pten overexpression rescues cortical defects caused by FOXJ3 deficiency. FCD-associated variant fails to upregulate Pten, leading to dysregulated mTOR signaling and enlarged neuronal soma, a hallmark of FCD. These findings suggest that mutations in FOXJ3 may cause epilepsy and FCD and define a transcriptional program that regulates the PTEN-mTOR pathway for neuronal specification and cortical lamination.
Tracy A. Bedrosian (Sat,) studied this question.