Fig 9. Kif13b regulates myelination in PNS and CNS through the Dlg1 scaffold.

The PI3K-AKT-mTOR signaling axis is one of the signaling pathways regulating myelination in both PNS and CNS, as recently reviewed [49–56,64]. Our results suggest that in Schwann cells, Kif13b is a positive regulator of myelination. Kif13b promotes p38γ MAPK-mediated Dlg1 phosphorylation and ubiquitination. Dlg1, in complex with PTEN, is known to reduce AKT activation and thus negatively regulates myelination. Dlg1 loss is associated with increased myelin thickness and myelin outfoldings, as a result of increased PIP₃ and AKT phosphorylation levels [8,9,47]. On the contrary, in oligodendrocytes, loss of Kif13b-mediated negative regulation of Dlg1 and the consequent increase in Dlg1 levels are associated with transient hypermyelination. Of note, we found that in the CNS Dlg1 is a promoter and not an inhibitor of myelination, and it likely modulates PI3K class I activity.