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Creation and preliminary characterization of a Tp53 knockout rat.

ABSTRACT: The tumor suppressor TP53 plays a crucial role in cancer biology, and the TP53 gene is the most mutated gene in human cancer. Trp53 knockout mouse models have been widely used in cancer etiology studies and in search for a cure of cancer with some limitations that other model organisms might help overcome. Via pronuclear microinjection of zinc finger nucleases (ZFNs), we created a Tp53 knockout rat that contains an 11-bp deletion in exon 3, resulting in a frameshift and premature terminations in the open reading frame. In cohorts of 25 homozygous (Tp53(?11/?11)), 37 heterozygous (Tp53(?11/+)) and 30 wild-type rats, the Tp53(?11/?11) rats lived an average of 126 days before death or removal from study because of clinical signs of abnormality or formation of tumors. Half of Tp53(?11/+) were removed from study by 1 year of age because of tumor formation. Both Tp53(?11/+) and Tp53(?11/?11) rats developed a wide spectrum of tumors, most commonly sarcomas. Interestingly, there was a strikingly high incidence of brain lesions, especially in Tp53(?11/?11) animals. We believe that this mutant rat line will be useful in studying cancer types rarely observed in mice and in carcinogenicity assays for drug development.

SUBMITTER: McCoy A

PROVIDER: S-EPMC3529357 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Creation and preliminary characterization of a Tp53 knockout rat.

McCoy Aaron A Besch-Williford Cynthia L CL Franklin Craig L CL Weinstein Edward J EJ Cui Xiaoxia X

Disease models & mechanisms 20120823 1

The tumor suppressor TP53 plays a crucial role in cancer biology, and the TP53 gene is the most mutated gene in human cancer. Trp53 knockout mouse models have been widely used in cancer etiology studies and in search for a cure of cancer with some limitations that other model organisms might help overcome. Via pronuclear microinjection of zinc finger nucleases (ZFNs), we created a Tp53 knockout rat that contains an 11-bp deletion in exon 3, resulting in a frameshift and premature terminations in ...[more]

PMID: 22917926

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Project description:The number of reported cases of neurodevelopmental disorders has increased significantly in the last few decades, but the etiology of these diseases remains poorly understood. There is evidence of a fundamental link between genetic abnormalities and symptoms of autism spectrum disorders (ASDs), and the most common monogenetic inheritable form of ASDs is Fragile X Syndrome (FXS). Previous studies indicate that FXS is linked to glutamate signaling regulation by the G-protein-coupled metabotropic glutamate receptor 5 (mGluR5), which has been shown to have a regulatory role in neuroinflammation. We characterized the effect of knocking out mGluR5 in an organism known to have complex cognitive functions-the rat. The heterozygous phenotype is the most clinically relevant; therefore, we performed analysis in heterozygous pups. We showed developmental abnormalities in heterozygous mGluR5 knockout rats, as well as a significant increase in chemokine (C-X-C motif) ligand 1 (CXCL) expression, a hallmark indicator of early onset inflammation. We quantified an increase in microglial density in the knockout pups and quantified morphological phenotypes representative of greater reactivity in the male vs. female and postnatal day 28 heterozygous pups compared to postnatal day 14 heterozygous pups. In response to injury, reactive microglia release matrix metalloproteases, contribute to extracellular matrix (ECM) breakdown, and are responsible for eradicating cellular and molecular debris. In our study, the changes in microglial density and reactivity correlated with abnormalities in the mRNA expression levels of ECM proteins and with the density of perineuronal nets. We saw atypical neuropsychiatric behavior in open field and elevated plus tests in heterozygous pups compared to wild-type litter and age-matched controls. These results demonstrate the pathological potential of the mGluR5 knockout in rats and further support the presence of neuroinflammatory roots in ASDs.

Dataset Information

Creation and preliminary characterization of a Tp53 knockout rat.

Publications

Creation and preliminary characterization of a Tp53 knockout rat.

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