Editors' ChoiceNeuroscience

A Notch Closer to Understanding Multiple Sclerosis

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Sci. Signal.  11 Feb 2014:
Vol. 7, Issue 312, pp. ec39
DOI: 10.1126/scisignal.2005167

Oligodendrocytes produce myelin, an electrically insulating coating on axons. Failure of oligodendrocyte precursor cells (OPCs) to mature leads to demyelination and axonal loss, as seen in multiple sclerosis (MS). After demyelinating injury, reactive astrocytes secrete the vasoconstrictor endothelin-1 (ET-1). Using a lysolecithin [or lysophosphatidyl choline (LPC)] mouse model of focal demyelination, Hammond et al. investigated the role of ET-1 in myelination. The abundance of ET-1 in reactive astrocytes increased in LPC-injected tissue. Addition of exogenous ET-1 decreased the number of mature oligodendrocytes (Olig2- and MAG-positive cells), whereas inducible knockdown of ET-1 in astrocytes after LPC injection increased the number of mature oligodendrocytes in demyelinated lesions, together indicating that astrocyte-derived ET-1 is an inhibitor of OPC differentiation. LPC lesions also had increased abundance of Jagged1, a Notch-1 ligand. Primary astrocyte cultures treated with ET-1 had increased abundance of Jagged1, an effect that was blocked with the ET receptor antagonist PD142,893. In a transgenic Notch reporter (TNR) mouse, the abundance of Jagged1 and of Notch intracellular cleaved domain (a marker of activated Notch) and the number of reactive astrocytes were increased in LPC lesions, and the peak abundance of ET-1 immediately preceded the peak of Notch activation after demyelinating injury. Infusion of LPC lesions in TNR mice with PD142,893 reduced Notch activation and increased the maturation of OPCs; both effects were reversed by addition of Jagged1. Additionally, the abundance of myelination markers and the thickness of myelin increased in PD142,893-treated LPC lesions. Coculture of OPCs from the TNR mouse and ET-1 pretreated astrocytes increased Notch activation in OPCs and markedly decreased the formation of mature oligodendrocytes, and both effects were blocked by treating cocultures with PD142,893. Together, the findings suggest that an ET receptor antagonist may be a new therapeutic option for MS.

T. R. Hammond, A. Gadea, J. Dupree, C. Kerninon, B. Nait-Oumesmar, A. Aguirre, V. Gallo, Astrocyte-derived endothelin-1 inhibits remyelination through Notch activation. Neuron 81, 588–602 (2014). [PubMed]