Fibroblast growth factor blocks Sonic hedgehog signaling in neuronal precursors and tumor cells.
The Sonic hedgehog (Shh) and FGF signaling pathways regulate growth and differentiation in many regions of the nervous system, but interactions between these pathways have not been studied extensively. Here, we examine the relationship between Shh and FGF signaling in granule cell precursors (GCPs), which are the most abundant neural progenitors in the cerebellum and the putative cell of origin for the childhood brain tumor medulloblastoma. In these cells, Shh induces a potent proliferative response that is abolished by coincubation with basic FGF. FGF also inhibits transcription of Shh target genes and prevents activation of a Gli-responsive promoter in fibroblasts, which suggests that it blocks Shh signaling upstream of Gli-mediated transcription. FGF-mediated inhibition of Shh responses requires activation of FGF receptors and of ERK and JNK kinases, because it can be blocked by inhibitors of these enzymes. Finally, FGF promotes differentiation of GCPs in vitro and in vivo and halts proliferation of tumor cells from patched (ptc) mutant mice, a model for medulloblastoma. These findings suggest that FGF is a potent inhibitor of Shh signaling and may be a useful therapy for tumors involving activation of the hedgehog pathway.
Fogarty
Marie P
MP
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Emmenegger
Brian A
BA
Grasfeder
Linda L
LL
Oliver
Trudy G
TG
Wechsler-Reya
Robert J
RJ
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D053823:Hedgehog Proteins / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology
D053823:Hedgehog Proteins; D050505:Mutant Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D020928:Mitogen-Activated Protein Kinases