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.

Abstract

Kif13b is an unconventional kinesin that acts as a signaling molecule, regulating myelination via the Dlg1 scaffold in both Schwann cells (in the peripheral nervous system) and oligodendrocytes (in the central nervous system).

Author Summary

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. However, the signals regulating myelin formation and how they are integrated and controlled to achieve homeostasis are still poorly understood.

In Schwann cells, the Discs large 1 (Dlg1) protein is a known brake of myelination, which negatively regulates the amount of myelin produced so that myelin thickness is proportional to axonal diameter. In this paper, we report that in Schwann cells Dlg1 itself is tightly regulated to ensure proper myelination. We propose that Dlg1 function is further controlled by the Kif13b kinesin motor protein, which acts as a "brake of the brake" by downregulating Dlg1 activity. Surprisingly, we found that in oligodendrocytes Dlg1 is a positive and not a negative regulator of myelination. Thus, Kif13b-mediated negative regulation of Dlg1 ensures appropriate myelin production and thickness in the central nervous system. Our data further extend recently emerged unconventional roles for kinesins, which are usually implicated in cargo transport rather than in the modulation of signaling pathways. The elucidation of mechanisms regulating myelination may help to design specific approaches to favor re-myelination in demyelinating disorders in which this process is severely impaired.