| Abstract No.: | B-C2095 |
| Country: | Canada |
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| Title: | THE LINK BETWEEN QUAKING PROTEINS AND P53 IN THE MURINE CENTRAL NERVOUS SYSTEM |
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| Authors/Affiliations: | 1 Christina Gavino*; 1 Stephane Richard;
1 Lady Davis Institute/McGill University, Montreal, QC, Canada
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| Content: | Background: The study of demyelinating diseases such as Multiple Sclerosis has been greatly advanced with the use of mouse models. One such model, the dysmyelinating mouse quaking viable mice (qkv), has been studied for over 40 years. The mice display rapid tremors at postnatal day 10 and develop tonic-clonic seizures as adults. Homozygous qkv/qkv mice exhibit a severe hypomyelination of the central nervous system (CNS). The qkv mutation consists of a deletion within the qkI promoter that influences the expression of certain alternatively spliced products. The qkI gene encodes for the alternatively spliced KH domain RNA binding proteins QKI-5, -6, and -7. The qkv mutation results in the loss of expression of isoforms 6 and 7, which have been shown to regulate myelin basic protein (MBP) mRNA export as well as oligodendrocyte (OL) maturation.
The GLD-1 C. elegans homolog of QKI is known to associate with the p53 cep-1 mRNA and this influences its activity. It is likely that QKI proteins also serve the same function in mammalian cells. The Richard lab has identified the consensus sequence for the QKI Response Element (QRE), being NACUAAY-N(1-20)-UAAY. The p53 mRNA actually harbours a similar QRE within its 3กฏ-UTR (UAYUAAYnnnUAAY) that we have shown does indeed interact with the QKI isoforms in vitro.
Objective: To investigate QKI and p53 interactions in the CNS using mouse models.
Materials and methods: p53-/- mice were bred to qkv/qkv mice to generate p53-/- mice within the qkv/qkv background. Progeny were monitored closely for behavioural changes. CNS morphology of compound mutant mice was compared to that of the qkv/qkv mice and p53-/- mice using immunocytochemistry.
Results: Compound mutant qkv/qkv ;p53-/- mice have an earlier onset of seizures compared to qkv/qkv mice. qkv/qkv;p53-/- mice also exhibit an ataxic gait and loss of balance. Immunocytochemistry revealed CNS neurodegeneration in qkv/qkv ;p53-/- mice which is characterized by the loss of Purkinje cell bodies and dendritic arborization.
CONCLUSION
The results of this study suggest that QKI proteins may interact with p53 in vivo to regulate neuronal maintenance and survival.
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