COLORECTAL HYPERPLASIA AND INFLAMMATION IN KERATIN 8-DEFICIENT EVB/N MICE
COLORECTAL HYPERPLASIA AND INFLAMMATION IN KERATIN 8-DEFICIENT EVB/N MICE
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DOI：
10.1101/gad.8.24.2964
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发表时间：
1994-12-15
影响因子：
10.5
通讯作者：
WILSONHEINER, M
中科院分区：
文献类型：
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作者：
BARIBAULT, H;PENNER, J;WILSONHEINER, M
我们报道角蛋白8 （mK8）基因破坏导致FVB/N小鼠结直肠增生。肠道病变均累及盲肠、结肠和直肠，但不累及小肠。隐窝的伸长伴随着固有层和粘膜下层的炎症。临床检测的肝、肾和胰腺功能均在非病理性范围内，提示主要缺陷在于结肠上皮细胞。肝酶丙氨酸（AST）和天冬氨酸（ALT）转氨酶虽小但持续升高，脾脏重量增加70%。由于mK8（-/-）雌性的生育力明显降低，没有建立纯合子小鼠系。先前，我们报道了mK8（-）靶向突变导致（C57Bl/6x129Sv）小鼠的胚胎致死。这种遗传背景对mK8（-）突变表型的强烈影响强调了使用几种近交小鼠品系来揭示多基因对突变表型的贡献的重要性。结果表明，在FVB/N和C57Bl/6遗传背景下，K8/K18纤维功能的遗传修饰因子具有不同的活性，对胚胎发生和肠道功能完整性具有深远的影响。更重要的是，mK8（-/-）肠道上皮细胞数量的增加，而不是细胞破坏，与表皮角蛋白提供机械强度的已知功能形成对比。
We report that keratin 8 (mK8) gene disruption causes colorectal hyperplasia in FVB/N mice. The intestinal lesions affect uniformly the cecum, colon, and rectum but not the small intestine. The elongation of the crypts is accompanied by an inflammation of the lamina propria and submucosa. Hepatic, renal, and pancreatic functions tested in clinical assays are within nonpathological range, suggesting that the major defect lies in colonic epithelial cells. Still, small but consistent elevation in the hepatic enzymes alanine (AST) and asparate (ALT) aminotransferase are observed, along with a 70% increase in spleen weight. No homozygous mouse line has been established, because of a markedly reduced fertility of the mK8(-/-) females. Previously, we reported that the mK8(-) targeted mutation causes embryonic lethality in (C57Bl/6x129Sv) mice. This strong effect of the genetic background on the mK8(-) mutant phenotype emphasizes the importance of using several inbred mouse strains to reveal the polygenic contribution to mutant phenotypes. Our results demonstrate that genetic modifiers of K8/K18 filament functions, with profound effects on embryogenesis and gut functional integrity, are differentially active in the FVB/N and C57Bl/6 genetic backgrounds. More importantly, the increase in mK8(-/-) gut epithelial cell number, rather than cell disruption, contrasts with the known function of epidermal keratins in providing mechanical strength.