title: Distinct roles for fibroblast growth factor signaling in cerebellar development and medulloblastoma.
abstract: Cerebellar granule neurons are the most abundant neurons in the brain, and a critical element of the circuitry that controls motor coordination and learning. In addition, granule neuron precursors (GNPs) are thought to represent cells of origin for medulloblastoma, the most common malignant brain tumor in children. Thus, understanding the signals that control the growth and differentiation of these cells has important implications for neurobiology and neurooncology. Our previous studies have shown that proliferation of GNPs is regulated by Sonic hedgehog (Shh), and that aberrant activation of the Shh pathway can lead to medulloblastoma. Moreover, we have demonstrated that Shh-dependent proliferation of GNPs and medulloblastoma cells can be blocked by basic fibroblast growth factor (bFGF). But while the mitogenic effects of Shh signaling have been confirmed in vivo, the inhibitory effects of bFGF have primarily been studied in culture. Here, we demonstrate that mice lacking FGF signaling in GNPs exhibit no discernable changes in GNP proliferation or differentiation. In contrast, activation of FGF signaling has a potent effect on tumor growth: treatment of medulloblastoma cells with bFGF prevents them from forming tumors following transplantation, and inoculation of tumor-bearing mice with bFGF markedly inhibits tumor growth in vivo. These results suggest that activators of FGF signaling may be useful for targeting medulloblastoma and other Shh-dependent tumors.
authors.affiliation: Department of Pharmacology & Cancer Biology and Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Emmenegger
authors.forename: E I
authors.initials: EI
authors.lastname: Hwang
authors.forename: C
authors.initials: C
authors.lastname: Moore
authors.forename: S L
authors.initials: SL
authors.lastname: Markant
authors.forename: S N
authors.initials: SN
authors.lastname: Brun
authors.forename: J W
authors.initials: JW
authors.lastname: Dutton
authors.forename: T-A
authors.initials: TA
authors.lastname: Read
authors.forename: M P
authors.initials: MP
authors.lastname: Fogarty
authors.forename: A R
authors.initials: AR
authors.lastname: Singh
authors.forename: D L
authors.initials: DL
authors.lastname: Durden
authors.forename: C
authors.initials: C
authors.lastname: Yang
authors.forename: W L
authors.initials: WL
authors.lastname: McKeehan
authors.forename: R J
authors.initials: RJ
authors.lastname: Wechsler-Reya
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D002528:Cerebellar Neoplasms / Q000209:etiology / Q000473:pathology*; D002531:Cerebellum / Q000254:growth & development*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D053823:Hedgehog Proteins / Q000502:physiology; D008527:Medulloblastoma / Q000209:etiology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology
chemical_list: D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D016222:Fibroblast Growth Factor 2; C496349:Fgfr1 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1