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J. Cell Biol., Volume 140, Number 6, March 23, 1998 1441-1451

Lessons from Keratin 18 Knockout Mice: Formation of Novel Keratin Filaments, Secondary Loss of Keratin 7 and Accumulation of Liver-specific Keratin 8-Positive Aggregates

Thomas M. Magin,*Dagger Rolf Schröder,*§ Sabine Leitgeb,par Frederique Wanninger,* Kurt Zatloukal, Christine Grund,** and David W. Melton§

* Institut fuer Genetik, Abteilung Molekulargenetik, Dagger  Bonner Forum Biomedizin, § Neurologische Klinik und Poliklinik, Universitaet Bonn, 53117 Bonn, Germany; par  Institute of Cell and Molecular Biology, University of Edinburgh, Edinburgh EH9 3JR, United Kingdom;  Institut fuer Pathologie, Universitaet Graz, A-8036 Graz, Austria; ** Abteilung fuer Zellbiologie, Deutsches Krebsforschungszentrum, 69120 Heidelberg, Germany

Here, we report on the analysis of keratin 18 null mice. Unlike the ablation of K8, which together with K18 is expressed in embryonic and simple adult epithelia, K18 null mice are viable, fertile, and show a normal lifespan. In young K18 null mice, hepatocytes were completely devoid of keratin filaments. Nevertheless, typical desmosomes were formed and maintained. Old K18 null mice, however, developed a distinctive liver pathology with abnormal hepatocytes containing K8-positive aggregates. These stained positively for ubiquitin and MM120-1 and were identified as Mallory bodies, one hallmark of human alcoholic hepatitis. This is the first demonstration that the ablation of one keratin leads to the accumulation of its single partner. Another striking finding was the absence or drastic down regulation of K7 in several tissues despite its ongoing transcription. Moreover, K18 null mice revealed new insights in the filament-forming capacity of the tail-less K19 in vivo. Due to the unexpected secondary loss of K7, only K8/19 are expressed in the uterine epithelium of K18 null mice. Immunoelectron microscopy of this tissue demonstrated the presence of typical K8/19 IF, thus highlighting in vivo that K19 is a fully competent partner for K8.


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