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SHANK3 Regulates Intestinal Barrier Function Through Modulating ZO-1 Expression Through the PKCε-dependent Pathway

Wei, Shu-Chen MD, PhD*; Yang-Yen, Hsin-Fang PhD; Tsao, Po-Nien MD, PhD; Weng, Meng-Tzu MD, PhD§; Tung, Chien-Chih MD; Yu, Linda C. H. PhD; Lai, Liang-Chuan PhD¶,**; Hsiao, Jen-Hao MSc**; Chuang, Eric Y. PhD**,††; Shun, Chia-Tung MD, PhD‡‡; Ni, Yen-Hsuan MD, PhD; Xavier, Ramnik J. MD, PhD§§; Podolsky, Daniel K. MD, PhD‖‖; Yen, Jeffery J. Y. PhD¶¶; Wong, Jau-Min MD, PhD*

doi: 10.1097/MIB.0000000000001250
Original Basic Science Articles

Background: The integrity of the gut barrier in patients with inflammatory bowel disease is known to be impaired but the exact mechanisms remain mostly unknown. SHANK3 mutations are associated with autism, and patients with autism are known to have higher proportions of inflammatory bowel disease. Here, we explore the role of SHANK3 in inflammatory bowel disease, both in vivo and in vitro.

Methods: Dextran sulfate sodium colitis was induced in SHANK3 knockout mice. Transepithelial electrical resistance, paracellular permeability, and Salmonella invasion assays were used to evaluate epithelial barrier function, in vitro and in vivo. Expression of tight junction proteins, protein kinases, and MAP kinase phosphorylation changes were analyzed by immunoblotting after overexpression or knockdown of SHANK3 expression. SHANK3 expression in intestinal tissue from patients with Crohn's disease was analyzed by quantitative polymerase chain reaction and immunohistochemistry.

Results: SHANK3 knockout mice were more susceptible to dextran sulfate sodium. SHANK3 knockout resulted in a leaky epithelial barrier phenotype, as demonstrated by decreased transepithelial electrical resistance, increased paracellular permeability, and increased Salmonella invasion. Overexpression of SHANK3 enhanced ZO-1 expression, and knockdown of SHANK3 resulted in decreased expression of ZO-1. Regulation of ZO-1 expression by SHANK3 seems to be mediated through a PKCε-dependent pathway. SHANK3 expression correlated with ZO-1 and PKCε in colonic tissue of patients with Crohn's disease.

Conclusions: The expression level of SHANK3 affects ZO-1 expression and the barrier function in intestinal epithelial cells. This may provide novel insights in Crohn's disease pathogenesis and treatment.

Article first published online 5 September 2017.

*Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan;

Institutes of Molecular Biology, Academia Sinica, Taipei, Taiwan;

Department of Pediatrics, College of Medicine, National Taiwan University, Taipei, Taiwan;

§Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei, Taiwan;

Department of Integrated Diagnostics and Therapeutics, College of Medicine, National Taiwan University, Taipei, Taiwan;

Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, Taiwan;

**Bioinformatics and Biostatistics Core, Center of Genomic Medicine, National Taiwan University, Taipei, Taiwan;

††Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan;

‡‡Department of Pathology and Forensic Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan;

§§Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Boston, Massachusetts;

‖‖UT Southwestern Medical Center, Dallas, Texas; and

¶¶Institutes of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.

Address correspondence to: Jau-Min Wong, MD, PhD, Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, 7 Chung-Shan South Road, Taipei, Taiwan (e-mail: jmwong@ntu.edu.tw).

Supported by the National Science Council of Taiwan (NSC-98-2314-B-002-139-, NSC-99-2314-B-002-124-MY3, NSC-102-2314-B-002-038); Liver Disease Prevention and Treatment Research Foundation, Taiwan.

The authors have no conflict of interest to disclose.

Received October 26, 2016

Accepted May 07, 2017

© Crohn's & Colitis Foundation
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