a mouse model of acrodermatitis enteropathica loss of intestine zinc transporter zip4 (slc39a4) disrupts the stem cell niche and intestine integrity小鼠模型的肢皮炎enteropathica失去肠锌转运体zip4(slc39a4)扰乱了干细胞利基和肠道的完整性.pdfVIP

A Mouse Model of Acrodermatitis Enteropathica: Loss of Intestine Zinc Transporter ZIP4 (Slc39a4) Disrupts the Stem Cell Niche and Intestine Integrity 1 2 3 1,3 Jim Geiser , Koen J. T. Venken , Robert C. De Lisle , Glen K. Andrews * 1 Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America, 2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America, 3 Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, Kansas, United States of America Abstract Mutations in the human Zip4 gene cause acrodermatitis enteropathica, a rare, pseudo-dominant, lethal genetic disorder. We created a tamoxifen-inducible, enterocyte-specific knockout of this gene in mice which mimics this human disorder. We found that the enterocyte Zip4 gene in mice is essential throughout life, and loss-of-function of this gene rapidly leads to wasting and death unless mice are nursed or provided excess dietary zinc. An initial effect of the knockout was the reprogramming of Paneth cells, which contribute to the intestinal stem cell niche in the crypts. Labile zinc in Paneth cells was lost, followed by diminished Sox9 (sex determining region Y-box 9) and lysozyme expression, and accumulation of mucin, which is normally found in goblet cells. This was accompanied by dysplasia of the intestinal crypts and significantly diminished small intestine cell division, and attenuated mTOR1 activity in villus enterocytes, indicative of increased catabolic metabolism, and diminished protein synthesis. This was followed by disorganization of the absorptive epithelium. Elemental analyses of small int