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Help us improve our products. Sign up to take part. A Nature Research Journal. Here, we report that PIK3C3 deficiency in zebrafish results in intestinal injury and inflammation. In pik3c3 mutants, gut tube forms but fails to be maintained.
Gene expression analysis reveals that barrier-function-related inflammatory bowel disease IBD susceptibility genes e-cadherin , hnf4a , ttc7a are suppressed, while inflammatory response genes are stimulated in the mutants. Histological analysis shows neutrophil infiltration into mutant intestinal epithelium and the clearance of gut microbiota.
Yet, gut microorganisms appear dispensable as mutants cultured under germ-free condition have similar intestinal defects. Mechanistically, we show that PIK3C3 deficiency suppresses the formation of PI3P and disrupts the polarized distribution of cell-junction proteins in intestinal epithelial cells. The integrity of intestinal epithelium is established and maintained by cell junctions between epithelial cells and it is essential for the barrier function against gut microbes.
Genetic studies in animal models have identified genes involved in intestinal epithelial homeostasis. For example, intestinal specific knockout of adherens junction protein E-Cadherin encoded by the Cdh1 gene in mice disrupts the barrier function of intestine and induces epithelial cell death and defective bacterial defensing 3 , 4. Hnf4a hepatocyte nuclear factor 4 alpha is an epithelial transcription factor involved in the development of liver, intestine, and other tissues.