title: Critical roles of type III phosphatidylinositol phosphate kinase in murine embryonic visceral endoderm and adult intestine.
abstract: 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.
authors: Department of Medical Biology, Akita University Graduate School of Medicine, Akita 010-8543, Japan.
authors: Shunsuke
authors: S
authors: Takasuga
authors: Yasuo
authors: Y
authors: Horie
authors: Junko
authors: J
authors: Sasaki
authors: Ge-Hong
authors: GH
authors: Sun-Wada
authors: Nobuyuki
authors: N
authors: Kawamura
authors: Ryota
authors: R
authors: Iizuka
authors: Katsunori
authors: K
authors: Mizuno
authors: Satoshi
authors: S
authors: Eguchi
authors: Satoshi
authors: S
authors: Kofuji
authors: Hirotaka
authors: H
authors: Kimura
authors: Masakazu
authors: M
authors: Yamazaki
authors: Chihoko
authors: C
authors: Horie
authors: Eri
authors: E
authors: Odanaga
authors: Yoshiko
authors: Y
authors: Sato
authors: Shinsuke
authors: S
authors: Chida
authors: Kenji
authors: K
authors: Kontani
authors: Akihiro
authors: A
authors: Harada
authors: Toshiaki
authors: T
authors: Katada
authors: Akira
authors: A
authors: Suzuki
authors: Yoh
authors: Y
authors: Wada
authors: Hirohide
authors: H
authors: Ohnishi
authors: Takehiko
authors: T
authors: Sasaki
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism / Q000648:ultrastructure; D053595:Embryonic Stem Cells / Q000378:metabolism; D004707:Endoderm / Q000196:embryology / Q000378:metabolism* / Q000648:ultrastructure; D005260:Female; D020869:Gene Expression Profiling; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014781:Viscera / Q000196:embryology / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D018129:Phosphatidylinositol Phosphates; C106336:phosphatidylinositol 3,5-diphosphate; D019869:Phosphatidylinositol 3-Kinases; C116930:Pikfyve protein, mouse