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The Journal of Neuroscience, November 1, 2006, 26(44):11278-11286; doi:10.1523/JNEUROSCI.2677-06.2006

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Neurobiology of Disease
Rescuing qk^v Dysmyelination by a Single Isoform of the Selective RNA-Binding Protein QKI

Lixia Zhao,¹ Donghua Tian,¹ Mingjing Xia,¹ Wendy B. Macklin,² and Yue Feng¹

¹Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, and ²Department of Neurology, Northwestern University, Chicago, Illinois 60611

Correspondence should be addressed to Dr. Yue Feng, Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322. Email: yfeng{at}emory.edu

Alternative splicing of the qkI transcript generates multiple isoforms of the selective RNA-binding protein QKI, which play key roles in controlling the homeostasis of their mRNA targets. QKI deficiency in oligodendrocytes of homozygous quakingviable (qk^v/qk^v) mutant mice results in severe hypomyelination, indicating the essential function of QKI in myelinogenesis. However, the molecular mechanisms by which QKI controls myelination remain elusive. We report here that QKI-6 is the most abundant isoform in brain and is preferentially reduced in the qk^v/qk^v mutant during normal myelinogenesis. To test whether QKI-6 is the predominant isoform responsible for advancing CNS myelination, we developed transgenic mice that express Flag-QKI-6 specifically in the oligodendroglia lineage, driven by the proteolipid protein (PLP) promoter. When introduced into the qk^v/qk^v mutant, the QKI-6 transgene rescues the severe tremor and hypomyelination phenotype. Electron microscopic studies further revealed that the Flag-QKI-6 transgene is sufficient for restoring compact myelin formation with normal lamellar periodicity and thickness. Interestingly, Flag-QKI-6 preferentially associates with the mRNA encoding the myelin basic protein (MBP) and rescues MBP expression from the beginning of myelinogenesis. In contrast, Flag-QKI-6 binds the PLP mRNA with lower efficiency and has a minimal impact on PLP expression until much later, when the expression level of QKI-6 in the transgenic animal significantly exceeds what is needed for normal myelination. Together, our results demonstrate that QKI-6 is the major isoform responsible for CNS myelination, which preferentially promotes MBP expression in oligodendrocytes.

Key words: myelination; quakingviable; qk^v; myelin basic protein; MBP; proteolipid protein; PLP; QKI RNA-binding protein

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Received June 23, 2006; revised Sept. 17, 2006; accepted Sept. 22, 2006.

Correspondence should be addressed to Dr. Yue Feng, Department of Pharmacology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322. Email: yfeng{at}emory.edu

This article has been cited by other articles:

				Y. Chen, D. Tian, L. Ku, D. J. Osterhout, and Y. Feng The Selective RNA-binding Protein Quaking I (QKI) Is Necessary and Sufficient for Promoting Oligodendroglia Differentiation J. Biol. Chem., August 10, 2007; 282(32): 23553 - 23560. [Abstract] [Full Text] [PDF]

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