Cooperation between sonic hedgehog and fibroblast growth factor/MAPK signalling pathways in neocortical precursors

• DOI: 10.1242/dev.01027
• Publication Date: 2004-02-17T01:14:10Z
• Authors: Nicoletta Kessaris; Françoise Jamen; Lee L. Rubin; William D. Richar...
• Keywords: 0301 basic medicine; Receptor Protein-Tyrosine Kinases; Neocortex; Nerve Tissue Proteins; Oligodendrocyte Transcription Factor 2; Receptors, Fibroblast Growth Factor; Fibroblast Growth Factors; Mice; Oligodendroglia; 03 medical and health sciences; Basic Helix-Loop-Helix Transcription Factors; Trans-Activators; Animals; Fibroblast Growth Factor 2; Hedgehog Proteins; Receptor, Fibroblast Growth Factor, Type 1; Mitogen-Activated Protein Kinases; Signal Transduction

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.