Kif13b Regulates PNS and CNS Myelination through the Dlg1 Scaffold.

Peter J Brophy,Roberta Noseda,Alessandra Bolino,Klaus-Armin Nave,Stefano C Previtali,Marta Guerrero-Valero,Ana Cuenda,Valeria Alberizzi,Marilena Palmisano,Maria Laura Feltri,Richard L Huganir,Diane L Sherman

doi:10.1371/journal.pbio.1002440

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.

Highlights

Myelination is a multistep process that includes axon recognition and contact, ensheathment, and myelin biogenesis
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
Myelin is a multilayered extension of the Schwann and oligodendrocyte cell membranes, which wraps around neuronal axons to facilitate propagation of electric signals and to support axonal metabolism

Summary

Introduction

Myelination is a multistep process that includes axon recognition and contact, ensheathment, and myelin biogenesis. Another study independently reported that Dlg1-silenced Schwann cells in vitro showed migration defects and reduced expression of the polarity protein Par3 [8]. Silenced cells overcame their migration defect and myelinated, but the resulting myelin segments were thicker than those of controls, which indicated Dlg as a negative regulator of myelin sheath thickness [8]. This role was further assessed in vivo, as we and others subsequently reported that mouse nerves lacking Dlg expression in Schwann cells have hypermyelination, myelin outfoldings, and demyelination as a consequence of myelin instability [8,9]. Dlg is thought to act in complex with phosphatase and tensin homolog (PTEN) to reduce AKT (v-AKT murine thymoma viral oncogene homolog) activation; it is a brake on myelination [8]

Methods

Results

Discussion

Conclusion