Hes1 FUNCTIONS DOWNSTREAM OF GROWTH FACTORS TO MAINTAIN OLIGODENDROCYTE LINEAGE CELLS IN THE EARLY PROGENITOR STAGE

Expansion of the progenitor pool of oligodendrocytes (OLs) is a critical process for obtaining appropriate amounts of mature myelin-forming OLs in the developing and regenerating central nervous system. In vitro, fibroblast growth factor-2 (FGF2), together with platelet-derived growth factor (PDGF), is required to expand oligodendrocyte progenitor cells (OLPs) in an unlimited manner, maintaining them in the early progenitor stage. However, the intracellular mechanisms that prevent OLP maturation remain elusive. In order to investigate these mechanisms, we established a mouse OLP primary culture, which enabled us to undertake biochemical analyses. We found that the suppressive effects on maturation of early OLP to the late O4(+) progenitor by PDGF+FGF2 treatment was abrogated by Mek inhibitor, while transfecting cells with a constitutively active Mek1 construct prevented OLP maturation, suggesting that the Mek-Erk pathway is implicated in the effects of the growth factor treatment. The activation of Mek-Erk pathway promoted proliferation of OLP suggesting that cell cycle progression has suppressive effects to the maturation of OLP. Furthermore, molecular screening using DNA microarrays revealed that Hes1, a negative regulator of bHLH transcription factors, is one of the downstream molecules induced by PDGF+FGF2 treatment. We confirmed that forced activation of Mek-Erk pathway is sufficient to induce Hes1 expression and that Hes1, in turn, exerts suppressive effects on the maturation of OL lineage by itself. Our observations thus indicate that Mek-Erk pathway plays pivotal role in preventing early OLP maturation to late OLPs and the effect is mediated by cell cycle progression as well as Hes1 induction. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.