Endothelial SHANK3 regulates tight junctions in the neonatal mouse blood-brain barrier through β-Catenin signaling
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...
Saved in:
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-02-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56720-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823861811269599232 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Yong-Eun Kim |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-69688edb737b43f69e5f1ee2272b7945 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-69688edb737b43f69e5f1ee2272b79452025-02-09T12:44:56ZengNature PortfolioNature Communications2041-17232025-02-0116111710.1038/s41467-025-56720-1Endothelial SHANK3 regulates tight junctions in the neonatal mouse blood-brain barrier through β-Catenin signalingYong-Eun Kim0Minseong Kim1Sunwhi Kim2Raham Lee3Yusuke Ujihara4Esther Magdalena Marquez-Wilkins5Yong-Hui Jiang6Esther Yang7Hyun Kim8Changhoon Lee9Changwon Park10Il Hwan Kim11Department of Anatomy and Neurobiology, University of Tennessee Health Science CenterDepartment of Molecular and Cellular Physiology, Louisiana State University Health Science CenterDepartment of Anatomy and Neurobiology, University of Tennessee Health Science CenterDepartment of Molecular and Cellular Physiology, Louisiana State University Health Science CenterDepartment of Anatomy and Neurobiology, University of Tennessee Health Science CenterNeuroscience Institute, University of Tennessee Health Science CenterDepartment of Genetics, Pediatrics and Neuroscience, Yale University School of MedicineDepartment of Anatomy, College of Medicine, Korea UniversityDepartment of Anatomy, College of Medicine, Korea UniversityDepartment of Neuroscience, University of Texas Southwestern Medical CenterDepartment of Molecular and Cellular Physiology, Louisiana State University Health Science CenterDepartment of Anatomy and Neurobiology, University of Tennessee Health Science CenterAbstract 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.https://doi.org/10.1038/s41467-025-56720-1 |
| spellingShingle | 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 Endothelial SHANK3 regulates tight junctions in the neonatal mouse blood-brain barrier through β-Catenin signaling Nature Communications |
| title | Endothelial SHANK3 regulates tight junctions in the neonatal mouse blood-brain barrier through β-Catenin signaling |
| title_full | Endothelial SHANK3 regulates tight junctions in the neonatal mouse blood-brain barrier through β-Catenin signaling |
| title_fullStr | Endothelial SHANK3 regulates tight junctions in the neonatal mouse blood-brain barrier through β-Catenin signaling |
| title_full_unstemmed | Endothelial SHANK3 regulates tight junctions in the neonatal mouse blood-brain barrier through β-Catenin signaling |
| title_short | Endothelial SHANK3 regulates tight junctions in the neonatal mouse blood-brain barrier through β-Catenin signaling |
| title_sort | endothelial shank3 regulates tight junctions in the neonatal mouse blood brain barrier through β catenin signaling |
| url | https://doi.org/10.1038/s41467-025-56720-1 |
| work_keys_str_mv | AT yongeunkim endothelialshank3regulatestightjunctionsintheneonatalmousebloodbrainbarrierthroughbcateninsignaling AT minseongkim endothelialshank3regulatestightjunctionsintheneonatalmousebloodbrainbarrierthroughbcateninsignaling AT sunwhikim endothelialshank3regulatestightjunctionsintheneonatalmousebloodbrainbarrierthroughbcateninsignaling AT rahamlee endothelialshank3regulatestightjunctionsintheneonatalmousebloodbrainbarrierthroughbcateninsignaling AT yusukeujihara endothelialshank3regulatestightjunctionsintheneonatalmousebloodbrainbarrierthroughbcateninsignaling AT esthermagdalenamarquezwilkins endothelialshank3regulatestightjunctionsintheneonatalmousebloodbrainbarrierthroughbcateninsignaling AT yonghuijiang endothelialshank3regulatestightjunctionsintheneonatalmousebloodbrainbarrierthroughbcateninsignaling AT estheryang endothelialshank3regulatestightjunctionsintheneonatalmousebloodbrainbarrierthroughbcateninsignaling AT hyunkim endothelialshank3regulatestightjunctionsintheneonatalmousebloodbrainbarrierthroughbcateninsignaling AT changhoonlee endothelialshank3regulatestightjunctionsintheneonatalmousebloodbrainbarrierthroughbcateninsignaling AT changwonpark endothelialshank3regulatestightjunctionsintheneonatalmousebloodbrainbarrierthroughbcateninsignaling AT ilhwankim endothelialshank3regulatestightjunctionsintheneonatalmousebloodbrainbarrierthroughbcateninsignaling |