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Critical roles of type III phosphatidylinositol phosphate kinase in murine embryonic visceral endoderm and adult intestine
- Source :
- Proceedings of the National Academy of Sciences of the United States of America. 110(5)
- Publication Year :
- 2013
-
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.
- Subjects :
- Male
Time Factors
Inflammation
Phosphatidylinositol 3-Kinases
Biology
chemistry.chemical_compound
Mice
Phosphatidylinositol Phosphates
medicine
Animals
Phosphatidylinositol
Intestinal Mucosa
Cells, Cultured
Embryonic Stem Cells
Oligonucleotide Array Sequence Analysis
Mice, Knockout
Multidisciplinary
Microscopy, Confocal
Kinase
Reverse Transcriptase Polymerase Chain Reaction
Gene Expression Profiling
Endoderm
Apical membrane
Biological Sciences
Embryo, Mammalian
Inflammatory Bowel Diseases
Embryonic stem cell
Molecular biology
Intestines
Mice, Inbred C57BL
Microscopy, Electron
Viscera
medicine.anatomical_structure
chemistry
Epiblast
Female
RNA Interference
medicine.symptom
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 110
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....a59d5badaf5d85d283430d43a855a35b