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

Area of Science:

• Gastroenterology
• Cell Biology
• Neuroscience

Background:

• Gut barrier integrity is compromised in inflammatory bowel disease (IBD), but mechanisms are unclear.
• SHANK3 mutations link autism to increased IBD risk.
• This study investigates SHANK3's role in IBD pathogenesis.

Purpose of the Study:

• To explore the role of SHANK3 in inflammatory bowel disease (IBD).
• To investigate the in vivo and in vitro mechanisms by which SHANK3 influences gut barrier function.
• To determine the correlation between SHANK3 expression and gut barrier markers in Crohn's disease patients.

Main Methods:

• Induced dextran sulfate sodium (DSS) colitis in SHANK3 knockout mice.
• Assessed epithelial barrier function using transepithelial electrical resistance (TER), paracellular permeability, and Salmonella invasion assays.
• Analyzed tight junction protein expression (ZO-1), kinase activity, and SHANK3 expression in mouse models and human Crohn's disease tissue.

Main Results:

• SHANK3 knockout mice showed increased susceptibility to DSS colitis and impaired epithelial barrier function.
• SHANK3 deficiency decreased ZO-1 expression via a PKCε-dependent pathway, leading to a 'leaky gut' phenotype.
• SHANK3 expression positively correlated with ZO-1 and PKCε in Crohn's disease colonic tissues.

Conclusions:

• SHANK3 expression levels directly influence ZO-1 expression and intestinal epithelial barrier function.
• SHANK3 plays a critical role in maintaining gut barrier integrity.
• Findings suggest SHANK3 as a potential therapeutic target for Crohn's disease.