title: Quaking Regulates Neurofascin 155 Expression for Myelin and Axoglial Junction Maintenance.
abstract: RNA binding proteins required for the maintenance of myelin and axoglial junctions are unknown. Herein, we report that deletion of the Quaking (QKI) RNA binding proteins in oligodendrocytes (OLs) using Olig2-Cre results in mice displaying rapid tremors at postnatal day 10, followed by death at postnatal week 3. Extensive CNS hypomyelination was observed as a result of OL differentiation defects during development. The QKI proteins were also required for adult myelin maintenance, because their ablation using PLP-CreERT resulted in hindlimb paralysis with immobility at ∼30 d after 4-hydroxytamoxifen injection. Moreover, deterioration of axoglial junctions of the spinal cord was observed and is consistent with a loss of Neurofascin 155 (Nfasc155) isoform that we confirmed as an alternative splice target of the QKI proteins. Our findings define roles for the QKI RNA binding proteins in myelin development and maintenance, as well as in the generation of Nfasc155 to maintain healthy axoglial junctions.
  
  
  CONCLUSIONS
  Neurofascin 155 is responsible for axoglial junction formation and maintenance. Using a genetic mouse model to delete Quaking (QKI) RNA-binding proteins in oligodendrocytes, we identify QKI as the long-sought regulator of Neurofascin alternative splicing, further establishing the role of QKI in oligodendrocyte development and myelination. We establish a new role for QKI in myelin and axoglial junction maintenance using an inducible genetic mouse model that deletes QKI in mature oligodendrocytes. Loss of QKI in adult oligodendrocytes leads to phenotypes reminiscent of the experimental autoimmune encephalomyelitis mouse model with complete hindlimb paralysis and death by 30 d after induction of QKI deletion.
authors.affiliation: 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, and Departments of Oncology and Medicine, Montréal, Québec H3T 1E2, Canada, and.
authors.forename: Lama
authors.initials: L
authors.lastname: Darbelli
authors.affiliation: 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, and Departments of Oncology and Medicine, Montréal, Québec H3T 1E2, Canada, and.
authors.forename: Gillian
authors.initials: G
authors.lastname: Vogel
authors.affiliation: Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec H3A 0G4, Canada.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Almazan
authors.affiliation: 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, and Departments of Oncology and Medicine, Montréal, Québec H3T 1E2, Canada, and stephane.richard@mcgill.ca.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Richard
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000831:Animals, Newborn; D001259:Ataxia / Q000235:genetics; D001369:Axons; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics*; D005786:Gene Expression Regulation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000235:genetics*; D009414:Nerve Growth Factors / Q000096:biosynthesis* / Q000235:genetics*; D009457:Neuroglia; D009836:Oligodendroglia; D010243:Paralysis / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015815:Cell Adhesion Molecules; D009414:Nerve Growth Factors; C504593:Nfasc protein, mouse; C098217:Qk protein, mouse; D016601:RNA-Binding Proteins
keywords: Quaking; RNA-binding proteins; alternative splicing; axoglial junctions; myelin; neurofascin