title: Kif13b Regulates PNS and CNS Myelination through the Dlg1 Scaffold.
abstract: Microtubule-based kinesin motors have many cellular functions, including the transport of a variety of cargos. However, unconventional roles have recently emerged, and kinesins have also been reported to act as scaffolding proteins and signaling molecules. In this work, we further extend the notion of unconventional functions for kinesin motor proteins, and we propose that Kif13b kinesin acts as a signaling molecule regulating peripheral nervous system (PNS) and central nervous system (CNS) myelination. In this process, positive and negative signals must be tightly coordinated in time and space to orchestrate myelin biogenesis. Here, we report that in Schwann cells Kif13b positively regulates myelination by promoting p38γ mitogen-activated protein kinase (MAPK)-mediated phosphorylation and ubiquitination of Discs large 1 (Dlg1), a known brake on myelination, which downregulates the phosphatidylinositol 3-kinase (PI3K)/v-AKT murine thymoma viral oncogene homolog (AKT) pathway. Interestingly, Kif13b also negatively regulates Dlg1 stability in oligodendrocytes, in which Dlg1, in contrast to Schwann cells, enhances AKT activation and promotes myelination. Thus, our data indicate that Kif13b is a negative regulator of CNS myelination. In summary, we propose a novel function for the Kif13b kinesin in glial cells as a key component of the PI3K/AKT signaling pathway, which controls myelination in both PNS and CNS.
authors.affiliation: Division of Neuroscience, INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Noseda
authors.affiliation: Division of Neuroscience, INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: Guerrero-Valero
authors.affiliation: Division of Neuroscience, INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Alberizzi
authors.affiliation: Division of Neuroscience, INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.|Department of Neurology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Stefano C
authors.initials: SC
authors.lastname: Previtali
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Sherman
authors.affiliation: Hunter James Kelly Research Institute, Department of Biochemistry and Neurology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, United States of America.
authors.forename: Marilena
authors.initials: M
authors.lastname: Palmisano
authors.affiliation: The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Huganir
authors.affiliation: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Goettingen, Germany.
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Cuenda
authors.affiliation: Hunter James Kelly Research Institute, Department of Biochemistry and Neurology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, New York, United States of America.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Feltri
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brophy
authors.affiliation: Division of Neuroscience, INSPE-Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bolino
mesh_terms: D000818:Animals; D002490:Central Nervous System / Q000502:physiology*; D000074288:Discs Large Homolog 1 Protein; D016547:Kinesins / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009836:Oligodendroglia / Q000378:metabolism; D017933:Peripheral Nervous System / Q000502:physiology*; D000074407:SAP90-PSD95 Associated Proteins; D012583:Schwann Cells / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000074288:Discs Large Homolog 1 Protein; C000614189:Dlg1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D000074407:SAP90-PSD95 Associated Proteins; D048051:p38 Mitogen-Activated Protein Kinases; C587627:KIF13b protein, mouse; D016547:Kinesins