Novel Strain With No ADP-ribosyltransferase I Enzymatic Activity
JAX® NOTES Issue 491, Fall 2003
Stroke, an interruption of blood supply to the brain resulting in neuron loss, is the third leading cause of death and the leading cause of long-term disability in the adult population of the United States1. The most common cause of stroke is ischemia (vascular occlusion). The complex mechanism of neuronal degeneration resulting from ischemic brain injury involves a cascade of reactions and often includes DNA damage. Cellular response to external stressors that disrupt the integrity of DNA, such as oxidative stress, activates the nuclear enzyme ADP-ribosyltransferase I. The post-translational modification of proteins catalyzed by ADP-ribosyltransferase I acts to facilitate DNA repair.
Although ADP-ribosyltransferase I acts to facilitate DNA repair in instances of reversible cellular injury, over-activation of the enzyme in response to severe cellular injury, as in cerebral ischemia, significantly depletes intracellular NAD+ levels. In the selective neuronal subpopulations that are especially vulnerable to ischemic insult, such energy depletion results in cell death. Survival of neurons and recovery of neurological function after ischemic brain injury depends upon both the severity of the damage from the initial insult and the subsequent cellular response. ADP-ribosyltransferase I also plays a role in DNA stability, cell proliferation and apoptosis, and maintenance of telomere function.
Dr. Zhao-Qi Wang generated, and donated to The Jackson Laboratory, a targeted mutation mouse that produces no ADP-ribosyltransferase I enzymatic activity1, called 129S-Adprt1tm1Zqw (Stock Number 002779) (Figure 1). Although mice homozygous for the mutation are viable and fertile, the multiple functions of ADP-ribosyltransferase I are phenotypically evident. Genomic stability is impaired in null mice, as demonstrated by chromosomal abnormalities, shortened telomeres, and increased sister chromatid exchange. Proliferation of mutant primary embryonic fibroblasts in vitro is deficient, while in vivo, recovery of thymocyte numbers is delayed following whole body gamma-irradiation. Pancreatic islet cells are resistant to oxidant-induced apoptosis. Thirty percent of homozygotes develop spontaneous skin disease beginning at six months of age. Hair loss and erythematous patches progress to acanthosis, parakeratosis, spongiosis, and epidermal hyperplasia. The loss of ADP-ribosyltransferase I function also imparts a neuroprotective effect. Homozygous mutant mice are less susceptible than controls to acute and chronic damage from the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and exhibit reduced N-methyl-d-aspartate (NMDA) excitotoxicity.
Figure 1. 129S-Adprt1tm1Zqw (Stock Number 002779) mice produce no ADP-ribosyltransferase I enzymatic activity.
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Reference
1. Wang ZQ, Auer B, Stingl L, Berghammer H, Haidacher D, Schweiger M, Wagner EF. Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease. Genes Dev 1995; 9:509-520.
