Deficiency in class III PI3-kinase confers postnatal lethality with IBD-like features in zebrafish

Shaoyang Zhao, Jianhong Xia, Xiuhua Wu, Leilei Zhang, Pengtao Wang, Haiyun Wang, Heying Li, Xiaoshan Wang, Yan Chen, Jean Agnetti, Yinxiong Li, Duanqing Pei () and Xiaodong Shu ()
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Shaoyang Zhao: University of Science and Technology of China
Jianhong Xia: Chinese Academy of Sciences
Xiuhua Wu: Chinese Academy of Sciences
Leilei Zhang: Chinese Academy of Sciences
Pengtao Wang: Chinese Academy of Sciences
Haiyun Wang: Chinese Academy of Sciences
Heying Li: Chinese Academy of Sciences
Xiaoshan Wang: Chinese Academy of Sciences
Yan Chen: Chinese Academy of Sciences
Jean Agnetti: Chinese Academy of Sciences
Yinxiong Li: Chinese Academy of Sciences
Duanqing Pei: Chinese Academy of Sciences
Xiaodong Shu: Chinese Academy of Sciences

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract The class III PI3-kinase (PIK3C3) is an enzyme responsible for the generation of phosphatidylinositol 3-phosphate (PI3P), a critical component of vesicular membrane. 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. These results not only reveal a role of PIK3C3 in gut homeostasis, but also provide a zebrafish IBD model.

Date: 2018
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DOI: 10.1038/s41467-018-05105-8

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