John et al. show that a signaling pathway that controls oligodendrocyte maturation in the embryo might contribute to the pathogenesis of multiple sclerosis if it is reactivated in the adult.
Source: Nature Reviews Drug Discovery
What is good for the embryo is not necessarily good for the adult, as a new report in Nature Medicine illustrates. In this paper, John et al. show that a signalling pathway that controls oligodendrocyte maturation in the embryo might contribute to the pathogenesis of multiple sclerosis (MS) if it is reactivated in the adult.
MS is an inflammatory disease that causes progressive demyelination in the central nervous system. This initially causes a deficit in axonal conduction, and unless remyelination occurs, the axons eventually degenerate because they lack the trophic support that myelin provides. In the early stages of the disease, the lesions are repaired quite efficiently, but the capacity for remyelination declines with time. However, even the most advanced lesions contain oligodendrocyte precursors that should be able to repair the damage, so why do they lose this ability in the later stages of MS?
The authors considered what other factors at the lesion site might be interfering with remyelination. The cytokine TGF-ß1 (transforming growth factor-ß1) is known to be present, and reactive astrocytes have also been implicated in the pathogenesis of MS. To examine how these components might interact to prevent remyelination, John et al. used microarray analysis to find out how TGF-ß1 affects the gene-expression profile of astrocytes in vitro.
One factor that was found to be upregulated in the presence of TGF-ß1 was a protein called jagged 1. During normal development, jagged 1 acts as a ligand for Notch, which is expressed on the surface of immature oligodendrocytes. Binding of jagged 1 to Notch activates the expression of the basic helix–loop–helix transcription factor Hes5 in the oligodendrocyte precursors, and this prevents them from differentiating too early. The authors found that jagged 1 was expressed in active demyelinating lesions, but not in lesions in which remyelination was successful. This indicates that the jagged–Notch–Hes5 pathway is likely to be one of the factors that prevent the oligodendrocyte precursors in MS lesions from acquiring a mature myelinating phenotype.
Although TGF-ß1 is deleterious in terms of remyelination, blocking its activity altogether is not a viable option, because it also protects against inflammation. These new findings raise the possibility of intervention further downstream — for example, by interfering with Notch signalling — and this could lead to the development of new therapeutic strategies for the treatment of MS.
© 2002 Nature Publishing Group