Oligodendrocytes Promote Neuronal Survival and Axonal Length by Distinct Intracellular Mechanisms: A Novel Role for Oligodendrocyte-Derived Glial Cell Line-Derived Neurotrophic Factor

Abstract

Interactions of CNS cells lead to the establishment of complex neural systems. Specifically, oligodendrocytes form myelin sheaths around axons that enable rapid electrical conduction of impulses. Recent evidence has emerged that oligodendrocytes may also release trophic factors promoting neuronal survival. We therefore studied the effects of factors released from cells of the oligodendrocyte lineage on neuronal survival and also on the morphology of neurons. Neurons derived from rat embryonic cortices were cultured and exposed to media conditioned by oligodendrocyte precursor cells (OPCs) or differentiated oligodendrocytes. In line with previous studies, exposure of OPC and oligodendrocyte-conditioned media (OCM) increased survival, a phosphatidylinositol 3'-kinase (PI3kinase)/Akt-dependent phenomenon. In addition, exposure of neurons to OCM but not OPC conditioned media resulted in increased axonal length per neuron, as detected by antibodies to phosphorylated neurofilaments. OCM exposure resulted in activation of the MAPkinase/extracellular signal-regulated kinase pathway, inhibition of which significantly reduced oligodendrocyte-mediated enhancement of axonal length but, unlike PI3kinase inhibition, had no effect on neuronal survival. Furthermore, we identify glial cell line-derived neurotrophic factor (GDNF) production by differentiated oligodendrocytes and provide evidence that implicates GDNF in OCM-mediated axonal effects, independent of its effect on neuronal survival. Therefore, we have shown that factors released by OPCs and oligodendrocytes induce the activation of distinct intracellular pathways within neurons, which have different functional effects on the cell.

Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence

“…94,95 Fifth, a reduction in the number and function of oligodendrocytes is becoming apparent from ultrastructural, 96 morphometric 97,98 and microarray 99,100 studies. Given the role of oligodendrocytes in myelination and other aspects of neuronal and synaptic integrity, 97,101,102 their involvement in schizophrenia is likely to be inextricably linked to the neuronal alterations mentioned, and to the functional consequences thereof, but at present it is not clear which are primary changes and which are secondary. Moreover, oligodendrocytes are an especially vulnerable cell population to many insults, and molecular abnormalities of oligodendrocytes are reported in association with many CNS disorders not involving myelin directly.…”

Predifferentiated Embryonic Stem Cells Prevent Chronic Pain Behaviors and Restore Sensory Function Following Spinal Cord Injury in Mice

“…Similar improvements have been demonstrated by administration of neuroprotective agents (for example, MgCl 2 and vitamin B 3 ), suggesting that neuroprotective mechanisms may be involved (30,(57)(58)(59). Several studies have shown that media from neural cell cultures provides beneficial effects by transfer of neurotrophic factors (17,60). Indeed, in a recent follow-up study (unpublished observations), we showed that transplanted ES cells are a source of BDNF and IL-6 and increased cAMP in the injured host cells in the spinal cord.…”

Truncated Prion Protein and Doppel Are Myelinotoxic in the Absence of Oligodendrocytic PrPC

“…Because PrP C binds in vitro to the transmembrane and GPI-linked forms of NCAM (Schmitt-Ulms et al, 2001), it might contribute to the very same pathways. Alternatively, PrP C may instruct oligodendrocytes to release factors necessary for axonal survival (Wilkins et al, 2003). Direct toxicity of ⌬PrP and Dpl to oligodendrocytes seems to be unlikely, because we did not observe oligodendrocytic cell death or ultrastructural abnormalities in oligodendrocytes.…”