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First published online 11 February 2004
doi: 10.1242/dev.01027
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1 Wolfson Institute for Biomedical Research and Department of Biology,
University College London, Gower Street, London WC1E 6BT, UK
2 Curis, 61 Moulton Street, Cambridge, MA 02138, USA
Author for correspondence (e-mail:
w.richardson{at}ucl.ac.uk)
Accepted 5 December 2003
Sonic hedgehog (SHH) and fibroblast growth factor 2 (FGF2) can both induce neocortical precursors to express the transcription factor OLIG2 and generate oligodendrocyte progenitors (OLPs) in culture. The activity of FGF2 is unaffected by cyclopamine, which blocks Hedgehog signalling, demonstrating that the FGF pathway to OLP production is Hedgehog independent. Unexpectedly, SHH-mediated OLP induction is blocked by PD173074, a selective inhibitor of FGF receptor (FGFR) tyrosine kinase. SHH activity also depends on mitogen-activated protein kinase (MAPK) but SHH does not itself activate MAPK. Instead, constitutive activity of FGFR maintains a basal level of phosphorylated MAPK that is absolutely required for the OLIG2- and OLP-inducing activities of SHH. Stimulating the MAPK pathway with a retrovirus encoding constitutively active RAS shows that the requirement for MAPK is cell-autonomous, i.e. MAPK is needed together with SHH signalling in the cells that become OLPs.
Key words: FGF, SHH, MAPK, Embryonic neural stem cells, Cell fate specification, Neural development, Oligodendrocyte progenitors, Mouse
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