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.

KIF13B establishes a CAV1-enriched microdomain at the ciliary transition zone to promote Sonic hedgehog signalling

“…Although defects in ciliary TZ integrity and Shh signalling are hallmarks of many ciliopathies (see above), so far no disease-causing mutations have been identified in KIF13B. However, a recent study using mutant mice in which Kif13b was specifically ablated in Schwann cells or oligodendrocytes revealed a requirement for Kif13b in peripheral and central nervous system myelination 55 —processes known to involve primary cilia-mediated Shh signalling 56 57 58 59 60 . It will therefore be of interest to investigate potential Shh signalling defects in the conditional Kif13b mutant mice 55 .…”

Functions of p38 MAP Kinases in the Central Nervous System

“…Activated p38α in presynaptic VTA neurons phosphorylate GIRK Kir3.1 to decrease somatic excitability and exocytosis of dopamine, allowing for development of place aversion in a behavioral conditioning task (Ehrich et al, 2015). Anxiety-related behavioral phenotypes are not apparent in p38γ knockout mice (Pogozelski et al, 2009;Ittner et al, 2016;Noseda et al, 2016) and have not been addressed for in p38β or p38δ knockout mice (Beardmore et al, 2005;Sumara et al, 2009).…”

Regulation of ciliary membrane protein trafficking and signalling by kinesin motor proteins

“…A recent study using conditional Kif13b knockout mice showed how KIF13B through its interaction with DLG1 affects myelination positively in the peripheral nervous system but negatively in the central nervous system . Furthermore, DLG1 was reported to mediate recruitment of KIF13B to LRP1‐containing vesicles, forming a DLG1‐KIF13B‐LRP1‐complex, which in turn recruited UTRN .…”

“…Other reported binding partners or cargoes of KIF13B include CENTA1 [301,302], a phosphatidylinositol 3,4,5-triphosphate (PIP3)-binding protein that functions as a GTPase activating protein (GAP) for ARF6 [303]; the endothelial cell RTK VEGFR2 [304] and neuronal TRPV1 channels [305]. A recent study using conditional Kif13b knockout mice showed how KIF13B through its interaction with DLG1 affects myelination positively in the peripheral nervous system but negatively in the central nervous system [306]. Furthermore, DLG1 was reported to mediate recruitment of KIF13B to LRP1-containing vesicles, forming a DLG1-KIF13B-LRP1-complex, which in turn recruited UTRN [307].…”