Mid-gestational lethality in mice lacking keratin 8.

Abstract

Keratin 8 (mK8) and its partner keratin 18 (mK18) are the first intermediate filament proteins expressed during mouse embryogenesis. They are found in most extraembryonic and embryonic simple epithelia, including trophectoderm, visceral yolk sac, gastrointestinal tract, lungs, mammary glands, and uterus. We report that a targeted null mutation in the inK8 gene causes mid-gestational lethality. Mutant embryos are growth retarded and suffer from internal bleeding, with an abnormal accumulation of erythrocytes in fetal livers. The mK8-phenotype has 94% penetrance, with a few mice surviving into adulthood. We suggest that mK8/mK18 filaments are important for the integrity of the fetal liver, like specialized human epidermal keratins for the integrity of the epidermis. This phenotype in mice differs from the reported function of simple epithelium keratins in Xenopus at the gastrulation stage. In mice, mK8 fulfills a vital function at 12 days postcoitum.

Transfection of Keratin 18 Gene in Human Breast Cancer Cells Causes Induction of Adhesion Proteins and Dramatic Regression of Malignancy In vitro and In vivo

“…More is known about the physical connections between structure and adhesion. Interactions of keratin filaments in desmosomal plaques have been extensively described (11,12,16,28,29), and it is suggested that keratin filaments are necessary for proper structure and function of desmosomes (13). Thus, it is possible that K18 transfection might not only regenerate the keratin filaments but that these could also reorganize the desmosomes by recruiting the requisite proteins and promoting their resynthesis.…”

“…The two most important adhesive compartments in the epithelium are desmosomes and adhesion junctions (11). The structure-stabilizing parts of the cytoskeleton are anchored in these structures, which thus connect the skeletons of the cells involved and generate the high mechanical-loading capacity of epithelia (12,13).…”

Decreased levels of keratin 8 sensitize mice to streptozotocin‐induced diabetes

“…In mouse models, knock‐down or expression of mutant simple epithelial K8 or K18, phenocopy human conditions and cause or predispose to a range of pathologies and abnormalities in the organs where these keratins are expressed, such as in the intestine, liver and thymus 10, 15, 16. K8 knockout (K8 −/− ) in mice, for example, causes 50% embryonic lethality and leads to an ulcerative‐colitis‐like phenotype in the surviving mice 17, 18. Moreover, liver fragility is observed in both K8 −/− and K18 −/− as well as in K18 mutant mice, while K8 knockdown disrupts cell morphology and increases apoptosis in the thymus 7, 15.…”

Intermediate filament proteins of the liver: Emerging disease association and functions

“…In the case of K8, which was the first IF gene Animal Models. Although IF proteins have been known for many years, it has been difficult to elucidate a biological to be successfully targeted for disruption, 24 the phenotype of the mice that lack K8 depended on their genetic background. function for these proteins.…”

“…3,4 In addition, results of ex-spontaneous intrahepatic hemorrhage. 24 In addition, K8 disruption in an FVB/N mouse strain background was also assoperiments using antibody-induced collapse of keratin 12 and vimentin filaments 13 in cultured cells were discouraging be-ciated with hepatobiliary abnormalities, although the most prominent phenotype in that background involved the intescause of the lack of change in cell morphology, DNA synthesis, or cell migration. An important experiment that provided tine.…”