内皮素-1调节少突胶质细胞发育

Endothelin-1 Regulates Oligodendrocyte Development

Ana Gadea, Adan Aguirre, Tarik F. Haydar, and Vittorio Gallo

Center for Neuroscience Research, Children's Research Institute, Children's National Medical Center, Washington, DC 20010

Correspondence should be addressed to Dr. Vittorio Gallo, Center for Neuroscience Research, Children's National Medical Center, 111 Michigan Avenue Northwest, Washington, DC 20010. Email: vgallo@cnmcresearch.org

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⁺ to the O1⁺ 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.