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The Journal of Neuroscience, July 1, 2000, 20(13):4944-4953

Destabilization and Mislocalization of Myelin Basic Protein mRNAs in quaking Dysmyelination Lacking the QKI RNA-Binding Proteins

Zhenzhong Li, Youyi Zhang, Daqing Li, and Yue Feng

Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322

Quakingviable (qkv) is a well known dysmyelination mutation. Recently, the genetic lesion of qkv has been defined as a deletion 5' to the qkI gene, which results in the severe reduction of the qkI-encoded QKI RNA-binding proteins in myelin-producing cells. However, no comprehensive model has been proposed regarding how the lack of QKI leads to dysmyelination. We hypothesized that QKI binds to myelin protein mRNAs, and the lack of QKI causes posttranscriptional misregulation, which in turn leads to the loss of the corresponding myelin proteins. To test this hypothesis, we developed an RNase protection assay to directly measure the mRNA isoforms encoding the myelin basic proteins (MBPs) in the brain. Our result suggested that isoform-preferential destabilization of MBP mRNAs in the cytoplasm was responsible for the reduced MBPs in the qkv/qkv brain during early myelination. In addition, we detected markedly reduced MBP mRNAs in the qkv/qkv myelin fraction with concomitant accumulation of MBP mRNAs associated with membrane-free polyribosomes. Presumably, the impaired localization of MBP mRNAs to the myelin membrane may cause insufficient incorporation of the newly synthesized MBPs into the myelin sheath. Finally, we observed interactions between QKI and MBP mRNAs, and removing MBP 3'UTR significantly reduced QKI-binding. Taken together, these observations suggest that misregulation at multiple posttranscriptional steps is responsible for the severe reduction of MBPs in qkv dysmyelination, presumably because of the lack of interactions between MBP mRNAs and the QKI RNA-binding proteins.

Key words: myelination; myelin basic protein; mRNA degradation and localization; quakingviable; signal transduction activators of RNA; posttranscriptional regulation

Copyright © 2000 Society for Neuroscience  0270-6474/00/20134944-10$05.00/0


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