Endothelin-1 Regulates Oligodendrocyte Development

Abstract

In the postnatal brain, oligodendrocyte progenitor cells (OPCs) arise from the subventricular zone (SVZ) and migrate into the developing white matter, where they differentiate into oligodendrocytes and myelinate axons. The mechanisms regulating OPC migration and differentiation are not fully defined. The present study demonstrates that endothelin-1 (ET-1) is an astrocyte-derived signal that regulates OPC migration and differentiation. OPCs in vivo and in culture express functional ET A and ET B receptors, which mediate ET-1-induced ERK (extracellular signal-regulated kinase) and CREB (cAMP response element-binding protein) phosphorylation. ET-1 exerts both chemotactic and chemokinetic effects on OPCs to enhance cell migration; it also prevents lineage progression from the O4 ϩ to the O1 ϩ stage without affecting cell proliferation. Astrocyte-conditioned medium stimulates OPC migration in culture through ET receptor activation, whereas multiphoton time-lapse imaging shows that selective ET receptor antagonists or anti-ET-1 antibodies inhibit OPC migration from the SVZ. Inhibition of ET receptor activity also derepresses OPC differentiation in the corpus callosum in slice cultures. Our findings indicate that ET-1 is a soluble astrocyte-derived signal that regulates OPC migration and differentiation during development.

Trans-regulation of oligodendrocyte myelination by neurons through small GTPase Arf6-regulated secretion of fibroblast growth factor-2

“…The results showed that the numbers of Olig2/BrdUdouble-positive cells are unchanged in the SVZ but are reduced in the Fim and CC in the N-Arf6-CKO mice. These results led to the conclusion that neuronal Arf6 plays an important role in OPC migration from the SVZ to the Fim and CC but not in NSC proliferation/differentiation, consistent with reports that OPCs differentiated from NSCs in the SVZ migrate to target areas in the postnatal brain [19][20][21][22][23] . However, it is still possible that proliferative NSCs in brain regions other than the SVZ differentiate into OPCs that migrate to the Fim and CC.…”

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

“…There are an increasing number of pathways and mechanisms being identified that could potentially play similar roles [85][86][87][88]. As previously indicated, such research could impact not only MS, but other myelin disorders, such as periventricular leukomalacia (PVL), in which a critical window for repair is inadequately addressed by current therapies.…”

A Versatile Murine Model of Subcortical White Matter Stroke for the Study of Axonal Degeneration and White Matter Neurobiology

“…Focal injection of ET-1 using the approach described here has been reported but endothelin-1 was shown to have direct paracrine effects on oligodendrocyte differentiation and maturation 10,18 confounding the study of post-stroke white matter biology. In contrast, the L-Nio approach targets endothelial cells alone while producing an identical lesion and eliminates any confounding paracrine effects on the cells involved in injury response.…”

“…The major advantages of this model are the use of a chemical endothelial nitric oxide synthase (eNOS) inhibitor N(5)-(1)-iminoethyl-L-ornithine HCl (L-Nio) 9 with no known paracrine effects on cellular elements of white matter which had been a complication of models using endothelin-1 10 . In addition, the stereotactic targeting of white matter in the mouse allows the use of any variety of transgenic or knockout strains, greatly expanding the available tools to determine the effect of stroke on brain white matter.…”