Scholarlink

<p>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 <i>FOXJ3</i> 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. <i>In utero</i> electroporation-mediated <i>Foxj3</i> 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 <i>Pten</i> as a key FOXJ3 target. Notably, <i>Pten</i> overexpression rescues cortical defects caused by FOXJ3 deficiency. FCD-associated variant fails to upregulate <i>Pten</i>, leading to dysregulated mTOR signaling and enlarged neuronal soma, a hallmark of FCD. These findings suggest that mutations in <i>FOXJ3</i> may cause epilepsy and FCD and define a transcriptional program that regulates the PTEN-mTOR pathway for neuronal specification and cortical lamination.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Epilepsy-associated FOXJ3 variants link a transcriptional program of the PTEN-mTOR pathway to neuronal specification and cortical lamination

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月9日

查看全文
  • Haw-Yuan Cheng,
  • Chen Liu,
  • Chiao-Wen Nien,
  • Hui-Chin Huang,
  • Hong-Jun Zhao,
  • Fang-Shin Nian,
  • Chien Chen,
  • Helena Martins Custodio,
  • Sanjay M. Sisodiya,
  • Chien Lu,
  • Hsin-Hung Chen,
  • Chih-Sin Hsu,
  • Wen-Chieh Pi,
  • Chia-Chi Chu,
  • Jacob Shu-Jui Hsu,
  • Pei-Lung Chen,
  • Fu-Pang Chang,
  • Chien-Yi Tung,
  • Shen-Ju Chou,
  • Shahryar Alavi,
  • Henry Houlden,
  • Wei-Yi Chen,
  • Yo-Tsen Liu,
  • Pei-Shan Hou,
  • Jin-Wu Tsai

摘要

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.