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Endothelial SHANK3 regulates tight junctions in the neonatal mouse blood-brain barrier through β-Catenin signaling

Author

Listed:
  • Yong-Eun Kim

    (University of Tennessee Health Science Center
    University of Tennessee Health Science Center)

  • Minseong Kim

    (Louisiana State University Health Science Center)

  • Sunwhi Kim

    (University of Tennessee Health Science Center
    University of Tennessee Health Science Center)

  • Raham Lee

    (Louisiana State University Health Science Center)

  • Yusuke Ujihara

    (University of Tennessee Health Science Center)

  • Esther Magdalena Marquez-Wilkins

    (University of Tennessee Health Science Center)

  • Yong-Hui Jiang

    (Yale University School of Medicine)

  • Esther Yang

    (Korea University)

  • Hyun Kim

    (Korea University)

  • Changhoon Lee

    (University of Texas Southwestern Medical Center)

  • Changwon Park

    (Louisiana State University Health Science Center)

  • Il Hwan Kim

    (University of Tennessee Health Science Center
    University of Tennessee Health Science Center)

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disability condition arising from a combination of genetic and environmental factors. Despite the blood-brain barrier (BBB) serving as a crucial gatekeeper, conveying environmental influences into the brain parenchyma, the contributions of BBB in ASD pathogenesis remain largely uncharted. Here we report that SHANK3, an ASD-risk gene, expresses in the BBB-forming brain endothelial cells (BECs) and regulates tight junctional (TJ) integrity essential for BBB’s barrier function. Endothelium-specific Shank3 (eShank3) knockout (KO) neonatal mice exhibit male-specific BBB-hyperpermeability, reduced neuronal excitability, and impaired ultra-sonic communications. Although BBB permeability is restored during adult age, the male mutant mice display reduced neuronal excitability and impaired sociability. Further analysis reveals that the BBB-hyperpermeability is attributed to the β-Catenin imbalance triggered by eShank3-KO. These findings highlight a pathogenic mechanism stemming from the ASD-risk Shank3, emphasizing the significance of neonatal BECs in the BBB as a potential therapeutic target for ASD.

Suggested Citation

  • Yong-Eun Kim & Minseong Kim & Sunwhi Kim & Raham Lee & Yusuke Ujihara & Esther Magdalena Marquez-Wilkins & Yong-Hui Jiang & Esther Yang & Hyun Kim & Changhoon Lee & Changwon Park & Il Hwan Kim, 2025. "Endothelial SHANK3 regulates tight junctions in the neonatal mouse blood-brain barrier through β-Catenin signaling," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56720-1
    DOI: 10.1038/s41467-025-56720-1
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    References listed on IDEAS

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    1. Kihoon Han & J. Lloyd Holder Jr & Christian P. Schaaf & Hui Lu & Hongmei Chen & Hyojin Kang & Jianrong Tang & Zhenyu Wu & Shuang Hao & Sau Wai Cheung & Peng Yu & Hao Sun & Amy M. Breman & Ankita Patel, 2013. "SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties," Nature, Nature, vol. 503(7474), pages 72-77, November.
    2. Claire S Leblond & Caroline Nava & Anne Polge & Julie Gauthier & Guillaume Huguet & Serge Lumbroso & Fabienne Giuliano & Coline Stordeur & Christel Depienne & Kevin Mouzat & Dalila Pinto & Jennifer Ho, 2014. "Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments," PLOS Genetics, Public Library of Science, vol. 10(9), pages 1-15, September.
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