A cytoplasmic quaking I isoform regulates the hnRNP F/H-dependent alternative splicing pathway in myelinating glia

• Type of Material: Article
• Authors: Mariana D. Mandler, Emory University; Li Ku, Emory University; Yue Feng, Emory University
• Language: English
• Date: 2014-07-01
• Publisher: Oxford University Press (OUP): Policy C - Option B
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://nar.oxfordjournals.org/content/42/11/7319
• Title of Journal or Parent Work: Nucleic Acids Research
• ISSN: 0305-1048
• Volume: 42
• Issue: 11
• Start Page: 7319
• End Page: 7329
• Grant/Funding Information: M.D.M. is also a trainee supported by the National Institutes of Health training grant T32G008367.; National Institutes of Health [NS053905 to Y.F., NS070526-01A1S1 to M.D.M.]; Source of open access funding: Funding for publication charges: National Institutes of Health.
• Research Categories: Health Sciences, Pharmacology

Abstract

The selective RNA-binding protein quaking I (QKI) plays important roles in controlling alternative splicing (AS). Three QKI isoforms are broadly expressed, which display distinct nuclear-cytoplasmic distribution. However, molecular mechanisms by which QKI isoforms control AS, especially in distinct cell types, still remain elusive. The quakingviable (qkv) mutant mice carry deficiencies of all QKI isoforms in oligodendrocytes (OLs) and Schwann cells (SWCs), the myelinating glia of central and peripheral nervous system (CNS and PNS), respectively, resulting in severe dysregulation of AS. We found that the cytoplasmic isoform QKI-6 regulates AS of polyguanine (G-run)-containing transcripts in OLs and rescues aberrant AS in the qkv mutant by repressing expression of two canonical splicing factors, heterologous nuclear ribonucleoproteins (hnRNPs) F and H. Moreover, we identified a broad spectrum of in vivo functional hnRNP F/H targets in OLs that contain conserved exons flanked by G-runs, many of which are dysregulated in the qkv mutant. Interestingly, AS targets of the QKI-6-hnRNP F/H pathway in OLs are differentially affected in SWCs, suggesting that additional cell-type-specific factors modulate AS during CNS and PNS myelination. Together, our studies provide the first evidence that cytoplasmic QKI-6 acts upstream of hnRNP F/H, which forms a novel pathway to control AS in myelinating glia.