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

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 () and Il Hwan Kim ()
Additional contact information
Yong-Eun Kim: University of Tennessee Health Science Center
Minseong Kim: Louisiana State University Health Science Center
Sunwhi Kim: 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

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-56720-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56720-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-56720-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().