COLORECTAL HYPERPLASIA AND INFLAMMATION IN KERATIN 8-DEFICIENT EVB N MICE/

We report that keratin 8 (mK8) gene disruption causes colorectal hyper plasia in FVB/N mice. The intestinal lesions affect uniformly the cecu m, colon, and rectum but not the small intestine. The elongation of th e crypts is accompanied by an inflammation of the lamina propria and s ubmucosa. Hepatic, renal, and pancreatic functions tested in clinical assays are within nonpathological range, suggesting that the major def ect lies in colonic epithelial cells. Still, small but consistent elev ation in the hepatic enzymes alanine (AST) and asparate (ALT) aminotra nsferase are observed, along with a 70% increase in spleen weight. No homozygous mouse line has been established, because of a markedly redu ced fertility of the mK8(-/-) females. Previously, we reported that th e mK8(-) targeted mutation causes embryonic lethality in (C57Bl/6x129S v) mice. This strong effect of the genetic background on the mK8(-) mu tant phenotype emphasizes the importance of using several inbred mouse strains to reveal the polygenic contribution to mutant phenotypes. Ou r results demonstrate that genetic modifiers of K8/K18 filament functi ons, with profound effects on embryogenesis and gut functional integri ty, are differentially active in the FVB/N and C57Bl/6 genetic backgro unds. More importantly, the increase in mK8(-/-) gut epithelial cell n umber, rather than cell disruption, contrasts with the known function of epidermal keratins in providing mechanical strength.