Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. No gene product (mRNA or protein) is detected by Northern or Western blot analysis of post partial hepatectomy liver tissue. Immediately following hepatectomy, homozygotes exhibit increased liver injury (increased necrosis and elevated liver enzymes) and delayed and diminished DNA synthesis. Induction of cyclin A and cyclin B1 expression in hepatocytes from posthepatectomy livers is delayed and decreased, cyclin E expression is decreased, induction of CCAAT enhancer binding protein (C/EBP) beta expression is absent, and activation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPL/ERK) is diminished. Elevated levels of activated matrix metalloproteinase (Mmp9) and active TGF-beta1 result with Fas agonist (Jo-2 mAb) challenge. Within 3 hours of Fas agonist treatment hepatocytes exhibit increased apoptosis and caspase activation, followed by hemorrhage and parenchymal degradation. Mutant mice suffer more rapid and severe hepatocellular injury due to acute carbon tetrachloride, CCl4, treatment, and DNA synthesis is delayed and diminished following treatment. This mutant mouse strain may be useful in studies of liver regen erat ion, acute viral hepatitis and mitogenic signaling pathways.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. As this allele was originally published on a mixed genetic background, it should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.