Critical roles of type III phosphatidylinositol phosphate kinase in murine embryonic visceral endoderm and adult intestine.

Shunsuke Takasuga, Yasuo Horie, Junko Sasaki, Ge-Hong Sun-Wada, Nobuyuki Kawamura, Ryota Iizuka, Katsunori Mizuno, Satoshi Eguchi, Satoshi Kofuji, Hirotaka Kimura, Masakazu Yamazaki, Chihoko Horie, Eri Odanaga, Yoshiko Sato, Shinsuke Chida, Kenji Kontani, Akihiro Harada, Akihiro Katada, Akira Suzuki, Yoh Wada, Hirohide Ohnishi and Takehiko Sasaki

Proceedings of the National Academy of Sciences of the United States of America 2013. 110: 1726-31.


The metabolism of membrane phosphoinositides is critical for a variety of cellular processes. Phosphatidylinositol-3,5-bisphosphate [PtdIns(3,5)P(2)] controls multiple steps of the intracellular membrane trafficking system in both yeast and mammalian cells. However, other than in neuronal tissues, little is known about the physiological functions of PtdIns(3,5)P(2) in mammals. Here, we provide genetic evidence that type III phosphatidylinositol phosphate kinase (PIPKIII), which produces PtdIns(3,5)P(2), is essential for the functions of polarized epithelial cells. PIPKIII-null mouse embryos die by embryonic day 8.5 because of a failure of the visceral endoderm to supply the epiblast with maternal nutrients. Similarly, although intestine-specific PIPKIII-deficient mice are born, they fail to thrive and eventually die of malnutrition. At the mechanistic level, we show that PIPKIII regulates the trafficking of proteins to a cell's apical membrane domain. Importantly, mice with intestine-specific deletion of PIPKIII exhibit diarrhea and bloody stool, and their gut epithelial layers show inflammation and fibrosis, making our mutants an improved model for inflammatory bowel diseases. In summary, our data demonstrate that PIPKIII is required for the structural and functional integrity of two different types of polarized epithelial cells and suggest that PtdIns(3,5)P(2) metabolism is an unexpected and critical link between membrane trafficking in intestinal epithelial cells and the pathogenesis of inflammatory bowel disease.

Our Thoughts on This Paper

This publication describes a study in which the PtdIns3P 5-kinase, PIPKIII (also known as PIKfyve and Fab1), is ablated. The whole body knock-out mice die around E8.5. The authors find profound defects in the embryonic visceral endoderm, an epithelial cell layer which provides nutrients to the growing embryo. These observations led the authors to generate an intestinal epithelia-specific knock-out line in order to test epithelial polarization and function in a well-characterized cell type. The resultant mice show dramatic defects in the morphology and membrane trafficking within the intestinal epithelia. Moreover, the intestinal dysfunction leads to early death and a phenotype with properties that are similar to Crohn's disease. In addition, the authors add to a growing body of literature that PIPKIII/Pikfyve is the sole source of PtdIns(3,5)P(2). Moreover, the intestinal epithelia joins a growing list of tissues affected by impaired PIPKIII function. The list includes the nervous system, heart, lung, kidney and spleen. The ability to generate additional lines in which PIPKIII/Pikfyve is conditionally ablated promises to expand knowledge of the roles of this signaling lipid in these and other tissues. This review was also published on F1000Prime at

Written by Dave Bridges on July 25, 2013.


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