ZFIN ID: ZDB-PUB-180708-1
Deficiency in class III PI3-kinase confers postnatal lethality with IBD-like features in zebrafish
Zhao, S., Xia, J., Wu, X., Zhang, L., Wang, P., Wang, H., Li, H., Wang, X., Chen, Y., Agnetti, J., Li, Y., Pei, D., Shu, X.
Date: 2018
Source: Nature communications   9: 2639 (Journal)
Registered Authors: Shu, Xiaodong
Keywords: none
Microarrays: GEO:GSE102032
MeSH Terms:
  • Animals
  • Animals, Newborn
  • Cadherins/metabolism
  • Cell Polarity
  • Disease Models, Animal
  • Embryo, Nonmammalian/metabolism
  • Embryo, Nonmammalian/pathology
  • Endocytosis
  • Enterocytes/pathology
  • Enterocytes/ultrastructure
  • Gastrointestinal Microbiome
  • Gastrointestinal Tract/pathology
  • Gene Expression Regulation, Developmental
  • Inflammation/pathology
  • Inflammatory Bowel Diseases/enzymology*
  • Inflammatory Bowel Diseases/pathology*
  • Larva/metabolism
  • Larva/ultrastructure
  • Mice
  • Mutation/genetics
  • Phosphatidylinositol 3-Kinase/deficiency*
  • Phosphatidylinositol 3-Kinase/metabolism
  • Phosphatidylinositol Phosphates/metabolism
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish/metabolism*
PubMed: 29980668 Full text @ Nat. Commun.
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.