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Nat. Commun., Published: 22 May 2025 | https://doi.org/10.1038/s41467-025-59838-4
The patient-specific mouse model with Foxg1 frameshift mutation provides insights into the pathophysiology of FOXG1 syndrome
Shin Jeon1,2,3,9, Jaein Park1,2,9, Ji Hwan Moon1,2,4,9, Dongjun Shin1,2, Liwen Li1,2, Holly O’Shea1,2, Seon-Ung Hwang1,2, Hyo-Jong Lee5, lise Brimble6,7, Jae W. Lee1,2, Stewart D. Clark8 & Soo-Kyung Lee1,2
1Department of Biological Sciences, College of Arts and Sciences, University at Buffalo, The State University of New York (SUNY), Buffalo, New York, USA.
2FOXG1 Research Center, University at Buffalo, The State University of New York (SUNY), Buffalo, NY, USA.
3Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
4Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.
5School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, South Korea.
6FOXG1 Research Foundation, Port Washington, New York, USA.
7Citizen Health, San Francisco, California, USA.
8Department of Pharmacology and Toxicology, University at Buffalo, The State University of New York (SUNY), Buffalo, NY, USA.
9These authors contributed equally: Shin Jeon, Jaein Park, Ji Hwan Moon.
Corresponding authors
Correspondence to Shin Jeon or Soo-Kyung Lee.
1Department of Biological Sciences, College of Arts and Sciences, University at Buffalo, The State University of New York (SUNY), Buffalo, New York, USA.
2FOXG1 Research Center, University at Buffalo, The State University of New York (SUNY), Buffalo, NY, USA.
3Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.
4Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.
5School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do, South Korea.
6FOXG1 Research Foundation, Port Washington, New York, USA.
7Citizen Health, San Francisco, California, USA.
8Department of Pharmacology and Toxicology, University at Buffalo, The State University of New York (SUNY), Buffalo, NY, USA.
9These authors contributed equally: Shin Jeon, Jaein Park, Ji Hwan Moon.
Corresponding authors
Correspondence to Shin Jeon or Soo-Kyung Lee.
Abstract
Single allelic mutations in the FOXG1 gene lead to FOXG1 syndrome (FS). To understand the pathophysiology of FS, which vary depending on FOXG1 mutation types, patient-specific animal models are critical. Here, we report a patient-specific Q84Pfs heterozygous (Q84Pfs-Het) mouse model, which recapitulates various FS phenotypes across cellular, brain structural, and behavioral levels. Q84Pfs-Het cortex shows dysregulations of genes controlling cell proliferation, neuronal projection and migration, synaptic assembly, and synaptic vesicle transport. The Q84Pfs allele produces the N-terminal fragment of FOXG1 (Q84Pfs protein) in Q84Pfs-Het mouse brains, which forms intracellular speckles, interacts with FOXG1 full-length protein, and triggers the sequestration of FOXG1 to distinct subcellular domains. Q84Pfs protein promotes the radial glial cell identity and suppresses neuronal migration in the cortex. Our study uncovers the role of the FOXG1 fragment from FS-causing FOXG1 variants and identifies the genes involved in FS-like cellular and behavioral phenotypes, providing insights into the pathophysiology of FS.
논문정보
- Research article
- 2025년 05월 (BRIC 등록일 2025-05-28)
- 국내+국외 연구진
- 생명과학 > 신경생물학
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