The QKI-6 and QKI-7 RNA binding proteins block proliferation and promote Schwann cell myelination.
BACKGROUND
The quaking viable (qk(v)) mice have uncompacted myelin in their central and peripheral nervous system (CNS, PNS). The qk gene encodes 3 major alternatively spliced isoforms that contain unique sequence at their C-terminus dictating their cellular localization. QKI-5 is a nuclear isoform, whereas QKI-6 and QKI-7 are cytoplasmic isoforms. The qk(v) mice harbor an enhancer/promoter deletion that prevents the expression of isoforms QKI-6 and QKI-7 in myelinating cells resulting in a dysmyelination phenotype. It was shown that QKI regulates the differentiation of oligodendrocytes, the myelinating cells of the CNS, however, little is known about the role of the QKI proteins, or RNA binding proteins in PNS myelination.


RESULTS
To define the role of the QKI proteins in PNS myelination, we ectopically expressed QKI-6 and QKI-7 in primary rat Schwann cell/neuron from dorsal root ganglia cocultures. We show that the QKI isoforms blocked proliferation and promoted Schwann cell differentiation and myelination. In addition, these events were coordinated with elevated proteins levels of p27(KIP1) and myelin basic protein (MBP), markers of Schwann cell differentiation. QKI-6 and QKI-7 expressing co-cultures contained myelinated fibers that had directionality and contained significantly thicker myelin, as assessed by electron microscopy. Moreover, QKI-deficient Schwann cells had reduced levels of MBP, p27(KIP1) and Krox-20 mRNAs, as assessed by quantitative RT-PCR.


CONCLUSIONS
Our findings suggest that the QKI-6 and QKI-7 RNA binding proteins are positive regulators of PNS myelination and show that the QKI RNA binding proteins play a key role in Schwann cell differentiation and myelination.
Larocque
Daniel
D
Terry Fox Molecular Oncology Group and the Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research, Sir Mortimer B Davis Jewish General Hospital, Department of Oncology and Medicine, McGill University, Montréal, Québec, Canada.
Fragoso
Gabriela
G
Huang
Jinghan
J
Mushynski
Walter E
WE
Loignon
Martin
M
Richard
Stéphane
S
Almazan
Guillermina
G
D017398:Alternative Splicing; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D051767:Early Growth Response Protein 2 / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism; D051379:Mice; D004676:Myelin Basic Protein / Q000378:metabolism; D009186:Myelin Sheath / Q000737:chemistry*; D017933:Peripheral Nervous System / Q000502:physiology; D020033:Protein Isoforms; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D051381:Rats; D012583:Schwann Cells / Q000378:metabolism*
D051767:Early Growth Response Protein 2; D004676:Myelin Basic Protein; D020033:Protein Isoforms; C098217:Qk protein, mouse; C522776:Qk protein, rat; D016601:RNA-Binding Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27