Search

Oligodendrocytes, the myelin-forming cells in the central nervous system (CNS), undergo morphological differentiation characterized by elaborated branched processes to enwrap neuronal axons. However, the basic molecular mechanisms underlying oligodendrocyte morphogenesis remain unknown. Herein, we describe the essential roles of Nuclear Distribution E Homolog 1 (NDE1), a dynein cofactor, in oligodendrocyte morphological differentiation. In the mouse corpus callosum, Nde1 mRNA expression was detected in oligodendrocyte lineage cells at the postnatal stage. In vitro analysis revealed that downregulation of NDE1 by siRNA impaired the outgrowth and extensive branching of oligodendrocyte processes and led to a decrease in the expression of myelin-related markers, namely, CNPase and MBP. In myelinating co-cultures with dorsal root ganglion (DRG) neurons, NDE1-knockdown oligodendrocyte precursor cells (OPCs) failed to develop into MBP-positive oligodendrocytes with multiple processes contacting DRG axons. Immunoprecipitation studies showed that NDE1 interacts with the dynein intermediate chain (DIC) in oligodendrocytes, and an overexpressed DIC-binding region of NDE1 exerted effects on oligodendrocyte morphogenesis that were similar to those following NDE1 knockdown. Furthermore, NDE1-knockdown-impaired oligodendrocyte process formation was rescued by siRNA-resistant wild-type NDE1 but not by DIC-binding region-deficient NDE1 overexpression. These results suggest that NDE1 plays a crucial role in oligodendrocyte morphological differentiation via interaction with dynein.

Repeated stressful events are associated with the onset of major depressive disorder (MDD). We previously showed oligodendrocyte (OL)-specific activation of the serum/glucocorticoid-regulated kinase (SGK)1 cascade, increased expression of axon-myelin adhesion molecules and elaboration of the oligodendrocytic arbor in the corpus callosum of chronically stressed mice. In the current study, we demonstrate that the nodes and paranodes of Ranvier in the corpus callosum were narrower in these mice. Chronic stress also led to diffuse redistribution of Caspr and Kv 1.1 and decreased the activity in white matter, suggesting a link between morphological changes in OLs and inhibition of axonal activity. OL primary cultures subjected to chronic stress resulted in SGK1 activation and translocation to the nucleus, where it inhibited the transcription of metabotropic glutamate receptors (mGluRs). Furthermore, the cAMP level and membrane potential of OLs were reduced by chronic stress exposure. We showed by diffusion tensor imaging that the corpus callosum of patients with MDD exhibited reduced fractional anisotropy, reflecting compromised white matter integrity possibly caused by axonal damage. Our findings suggest that chronic stress disrupts the organization of the nodes of Ranvier by suppressing mGluR activation in OLs and that specific white matter abnormalities are closely associated with MDD onset.