PTEN Phosphohydrolase; TOR Serine-Threonine Kinases; Forkhead Transcription Factors; PTEN protein, human; MTOR protein, human; Pten protein, mouse; Animals; Mice; Humans; Signal Transduction/genetics; Female; Male; Mutation; Cell Movement/genetics; Malformations of Cortical Development, Group I/genetics; PTEN Phosphohydrolase/metabolism; PTEN Phosphohydrolase/genetics; TOR Serine-Threonine Kinases/metabolism; TOR Serine-Threonine Kinases/genetics; Forkhead Transcription Factors/genetics; Forkhead Transcription Factors/metabolism; Neurons/metabolism; Neurons/pathology; Cerebral Cortex/metabolism; Cerebral Cortex/pathology; Cerebral Cortex/embryology; Epilepsy/genetics; Epilepsy/metabolism; Cell Movement; Cerebral Cortex; Epilepsy; Focal cortical dysplasia of Taylor; Malformations of Cortical Development, Group I; Neurons; Signal Transduction; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Multidisciplinary; Physics and Astronomy (all)
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Cheng, Haw-Yuan ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Liu, Chen; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Nien, Chiao-Wen; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Huang, Hui-Chin; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Zhao, Hong-Jun; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Nian, Fang-Shin ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
Chen, Chien; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan ; School of Medicine, National Yang Ming Chiao Tung University College of Medicine Taipei, Taipei, Taiwan ; Division of Epilepsy, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
Custodio, Helena Martins; Research Department of Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, and Chalfont Centre for Epilepsy, Buckinghamshire, London, UK
Sisodiya, Sanjay M ; Research Department of Epilepsy, UCL Queen Square Institute of Neurology, University College London, London WC1N 3BG, and Chalfont Centre for Epilepsy, Buckinghamshire, London, UK
Lu, Chien ; School of Medicine, National Yang Ming Chiao Tung University College of Medicine Taipei, Taipei, Taiwan
Chen, Hsin-Hung ; School of Medicine, National Yang Ming Chiao Tung University College of Medicine Taipei, Taipei, Taiwan ; Department of Neurosurgery, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan
Hsu, Chih-Sin; Genomics Center for Clinical and Biotechnological Applications, Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
Pi, Wen-Chieh ; Institute of Biochemistry and Molecular Biology, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
Chu, Chia-Chi; Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan
Hsu, Jacob Shu-Jui; Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan
Chen, Pei-Lung ; Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, Taiwan ; Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
Chang, Fu-Pang; Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
Tung, Chien-Yi ; Genomics Center for Clinical and Biotechnological Applications, Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
Chou, Shen-Ju ; Neuroscience Program of Academia Sinica (NPAS), Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
Alavi, Shahryar ; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK
Houlden, Henry ; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London, UK
Chen, Wei-Yi ; Institute of Biochemistry and Molecular Biology, College of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
Liu, Yo-Tsen; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. ytliu2@vghtpe.gov.tw ; School of Medicine, National Yang Ming Chiao Tung University College of Medicine Taipei, Taipei, Taiwan. ytliu2@vghtpe.gov.tw ; Division of Epilepsy, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan. ytliu2@vghtpe.gov.tw ; Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan. ytliu2@vghtpe.gov.tw
Hou, Pei-Shan; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. pshou@nycu.edu.tw ; Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan. pshou@nycu.edu.tw ; Institute of Anatomy and Cell Biology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. pshou@nycu.edu.tw
Tsai, Jin-Wu ; Institute of Brain Science, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan. tsaijw@nycu.edu.tw ; Brain Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan. tsaijw@nycu.edu.tw ; Advanced Therapeutics Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan. tsaijw@nycu.edu.tw ; Department of Biological Science and Technology, College of Engineering Bioscience, National Yang Ming Chiao Tung University, Hsinchu, Taiwan. tsaijw@nycu.edu.tw
The authors would like to thank all the affected individuals and their families participating in this study. This study was supported by grants from the National Science and Technology Council (NSTC, 108-2638-B-010-001-MY2, 108-2321-B-010-011-MY2, 110-2628-B-A49A-506, 111-2628-B-A49-016, 112-2628-B-A49-005, and 112-2314-B-A49-075), National Health Research Institutes (NHRI-EX109-10904NI), and the Brain Research Center, National Yang Ming Chiao Tung University (NYCU) through the Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) to JWT; NSTC (111-2314-B-A49-053-MY3), National Health Research Institutes (NHRI-EX113-11007NC) to PSH; and NSTC (107-2314-B-075-020, 109-2314-B-075-055, 110-2628-B-075-014, 112-2314-B-075-078, 113-2314-B-075-003, 113-2314-B-075-072-MY3), Taipei Veterans General Hospital (V108C-075) to YTL. HMC and SMS were supported by the Epilepsy Society; HMC was supported by the Amelia Roberts Fund. HYC is a Postdoctoral Researcher of Fund for Scientific Research \u2013 FNRS and supported by the Grant No. 40032806. The authors acknowledge the technical services provided by the National Genomics Center for Clinical and Biotechnological Applications of the Cancer and Immunology Research Center (NYCU), the National Core Facility for Biopharmaceuticals (NCFB), NSTC (113-2740-B-A49-002, 112-2740-B-A49-001, 111-2740-B-A49-001)
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