Editors' ChoiceNeuroscience

Signaling for Remyelination

Sci. Signal.  11 Jun 2013:
Vol. 6, Issue 279, pp. ec135
DOI: 10.1126/scisignal.2004410

Axons in the central nervous system are protected by myelin sheaths produced by oligodendrocytes. Demyelination is a feature of inflammatory neuropathies such as multiple sclerosis (MS). In experimental allergic encephalitis (EAE), a mouse model of MS, regions of demyelination and inflammation correlate with increased abundance of sirtuin 1 (SIRT1), a nuclear deacetylase. Using an inducible and selective SIRT1-knockout mouse (NestinCreER;Sirt1lox/lox), Rafalski et al. found that SIRT1 inactivation in adult neural stem cells (NSCs) induced the expansion of oligodendrocyte progenitor cells (OPCs). Compared with wild-type counterparts, the striatum and septum of NestinCreER;Sirt1lox/lox mice had a greater percentage of cells positive for OPC and oligodendrocyte marker proteins in vivo. Primary NestinCreER;Sirt1lox/lox NSCs and neural progenitors cultured in differentiation medium had many cells positive for these OPC and oligodendrocyte markers, as well as cells positive for the OPC-specific marker O4 and MBP (myelin basic protein), a marker of mature myelinating oligodendrocytes. Treating wild-type cultured NSCs with a SIRT1 catalytic inhibitor under differentiation conditions also increased the percentage of O4-positive cells. In contrast, the number of cells positive for neuron or astrocyte markers did not increase, suggesting that SIRT1 inactivation may selectively promote OPC expansion. Whole-genome microarrays of NSCs from NestinCreER;Sirt1lox/lox mice revealed that SIRT1 inactivation increased the expression of genes that encode proteins involved in growth factor signaling and cell metabolism, particularly PDGFRα (platelet-derived growth factor receptor α). Chromatin immunoprecipitation analysis showed increased acetylation of histone H3 at Lys9, a SIRT1 target, in the Pdgfrα promoter in NSC and neural progenitors cultured from NestinCreER;Sirt1lox/lox mice. Downstream kinases p38 mitogen-activated protein kinase (MAPK) and Akt were also activated in NSCs cultured from NestinCreER;Sirt1lox/lox mice, and pharmacologically inhibiting either of these pathways reduced or abolished the differentiation-induced generation of O4-positive OPCs from the cultured SIRT1-deficient NSCs. In contrast, inhibition of the ERK1 and ERK2 MAPK pathway had no effect. Furthermore, NestinCreER;Sirt1lox/lox mice showed increased remyelination in brain regions focally injected with lysolecithin, a demyelinating agent, and delayed EAE-induced paralysis compared with controls. Together, the findings suggest that inactivation of SIRT1 may promote oligodendrocyte differentiation and thus may be a target for improving symptoms of demyelinating disease.

V. A. Rafalski, P. P. Ho, J. O. Brett, D. Ucar, J. C. Dugas, E. A. Pollina, L. M. L. Chow, A. Ibrahim, S. J. Baker, B. A. Barres, L. Steinman, A. Brunet, Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. Nat. Cell Biol. 15, 614–624 (2013). [PubMed]