Epilepsy-associated FOXJ3 variants link a transcriptional program of the PTEN-mTOR pathway to neuronal specification and cortical lamination.
Journal
Nature communications
Journal Volume
17
Journal Issue
1
Start Page
Art. No. 1815
ISSN
2041-1723
Date Issued
2026-03-09
Author(s)
Cheng, Haw-Yuan
Liu, Chen
Nien, Chiao-Wen
Huang, Hui-Chin
Zhao, Hong-Jun
Nian, Fang-Shin
Chen, Chien
Custodio, Helena Martins
Sisodiya, Sanjay M
Lu, Chien
Chen, Hsin-Hung
Hsu, Chih-Sin
Pi, Wen-Chieh
Chu, Chia-Chi
Chang, Fu-Pang
Tung, Chien-Yi
Chou, Shen-Ju
Alavi, Shahryar
Houlden, Henry
Chen, Wei-Yi
Liu, Yo-Tsen
Hou, Pei-Shan
Tsai, Jin-Wu
Abstract
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.
Publisher
Nature Research
Type
journal article