Rescuing qk(v) dysmyelination by a single isoform of the selective RNA-binding protein QKI

• Type of Material: Article
• Authors: Lixia Zhao, Emory University; Donghua Tian, Emory University; Mingjing Xia, Emory University; Wendy B. Macklin, Northwestern University; Yue Feng, Emory University
• Language: English
• Date: 2006-11-01
• Publisher: Lippincott, Williams & Wilkins
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2006 Society for Neuroscience.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1523/JNEUROSCI.2677-06.2006
• Title of Journal or Parent Work: Journal of Neuroscience Nursing
• ISSN: 0888-0395
• Volume: 26
• Issue: 44
• Start Page: 11278
• End Page: 11286
• Keywords: SIGNAL-TRANSDUCTION; MYELIN BASIC-PROTEIN; Science & Technology; Life Sciences & Biomedicine; BRAIN; GENE; MOUSE; MESSENGER-RNAS; Neurosciences & Neurology; PROTEOLIPID PROTEIN; Neurosciences; PARKIN; QUAKING; EXPRESSION
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience

Abstract

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 (qkv/qkv) 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.Wereport here that QKI-6 is the most abundant isoform in brain and is preferentially reduced in the qkv/qkv 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/qkv 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 untilmuchlater, 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.