Rescuing qkV dysmyelination by a single isoform of the selective RNA-binding protein QKI.
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. We report 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 qkV/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 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.
Zhao
Lixia
L
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Tian
Donghua
D
Xia
Mingjing
M
Macklin
Wendy B
WB
Feng
Yue
Y
D000818:Animals; D003711:Demyelinating Diseases / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D051379:Mice; D008821:Mice, Quaking; D008822:Mice, Transgenic; D009185:Myelin Proteins / Q000096:biosynthesis / Q000235:genetics; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*
D009185:Myelin Proteins; D020033:Protein Isoforms; C098217:Qk protein, mouse; D016601:RNA-Binding Proteins