B6.129X1-Igfbp1^tm1Taub/J

Stock number: 005248
Product name: IGFBP-1-
Research areas: Cell Biology Research, Developmental Biology Research

Description

These Igfbp1 knock-out mice suffer more rapid and severe hepatocellular injury and delayed and diminished DNA synthesis after hepatectomy or toxic damage.

Detailed description

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.

Development

A targeting vector containing neomycin resistance gene driven by the mouse phosphoglycerate kinase promoter and a herpes simplex virus thymidine kinase gene was used to disrupt the first 234 bp of sequence encoding the promoter and exons 1 and 2. The construct was electroporated into 129X1/SvJ derived RW4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts. The resulting chimeric animals were crossed to C57BL/6J mice, and then backcrossed to the same for 11 generations.

Allele

Symbol: Igfbp1^tm1Taub
Name: targeted mutation 1, Rebecca Taub
MGI accession ID: MGI:2448461
Generation method: Targeted
Attributes: Null/Knockout
Synonyms: IGFBP-1^-
Marker symbol: Igfbp1
Marker name: insulin-like growth factor binding protein 1
Marker synonyms: AFBP; hIGFBP-1; IBP1; IGFBA; IGFBP-1; IGF-BP25; PP12
Chromosome: 11
Strain of origin: 129X1/SvJ
Molecular note: A sequence fragmenet encompassing 234 bp of the promoter and exons 1 and 2 was replaced with a PGK-neo cassette inserted by homologous recombination. Endogenous transcript was undetected by Northern blot analysis of homozygous mutant mice following partial hepatectomy. Western blot analysis of whole liver extracts from quiescent and 1 to 8 hour posthepatectomy homozygous mutant mice showed an absence of normal protein.