Quaking I controls a unique cytoplasmic pathway that regulates alternative splicing of myelin-associated glycoprotein.
Precise control of alternative splicing governs oligodendrocyte (OL) differentiation and myelination in the central nervous system (CNS). A well-known example is the developmentally regulated expression of splice variants encoding myelin-associated glycoprotein (MAG), which generates two protein isoforms that associate with distinct cellular components crucial for axon-glial recognition during myelinogenesis and axon-myelin stability. In the quakingviable (qk(v)) hypomyelination mutant mouse, diminished expression of isoforms of the selective RNA-binding protein quaking I (QKI) leads to severe dysregulation of MAG splicing. The nuclear isoform QKI-5 was previously shown to bind an intronic element of MAG and modulate alternative exon inclusion from a MAG minigene reporter. Thus, QKI-5 deficiency was thought to underlie the defects of MAG splicing in the qk(v) mutant. Surprisingly, we found that transgenic expression of the cytoplasmic isoform QKI-6 in the qk(v) OLs completely rescues the dysregulation of MAG splicing without increasing expression or nuclear abundance of QKI-5. In addition, cytoplasmic QKI-6 selectively associates with the mRNA that encodes heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), a well-characterized splicing factor. Furthermore, QKI deficiency in the qk(v) mutant results in abnormally enhanced hnRNPA1 translation and overproduction of the hnRNPA1 protein but not hnRNPA1 mRNA, which can be successfully rescued by the QKI-6 transgene. Finally, we show that hnRNPA1 binds MAG pre-mRNA and modulates alternative inclusion of MAG exons. Together, these results reveal a unique cytoplasmic pathway in which QKI-6 controls translation of the splicing factor hnRNPA1 to govern alternative splicing in CNS myelination.
Zhao
Lixia
L
Department of Pharmacology, School of Medicine, Emory University, Atlanta, GA 30322, USA.
Mandler
Mariana D
MD
Yi
Hong
H
Feng
Yue
Y
D017398:Alternative Splicing / Q000502:physiology*; D000818:Animals; D001369:Axons / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism*; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018992:Myelin-Associated Glycoprotein; D009457:Neuroglia / Q000378:metabolism; D014176:Protein Biosynthesis / Q000502:physiology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000235:genetics
D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C104739:Mag protein, mouse; D018992:Myelin-Associated Glycoprotein; D020033:Protein Isoforms; C098217:Qk protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D011956:Receptors, Cell Surface