title: N-myc is an essential downstream effector of Shh signaling during both normal and neoplastic cerebellar growth.
abstract: We examined the genetic requirements for the Myc family of oncogenes in normal Sonic hedgehog (Shh)-mediated cerebellar granule neuronal precursor (GNP) expansion and in Shh pathway-induced medulloblastoma formation. In GNP-enriched cultures derived from N-myc(Fl/Fl) and c-myc(Fl/Fl) mice, disruption of N-myc, but not c-myc, inhibited the proliferative response to Shh. Conditional deletion of c-myc revealed that, although it is necessary for the general regulation of brain growth, it is less important for cerebellar development and GNP expansion than N-myc. In vivo analysis of compound mutants carrying the conditional N-myc null and the activated Smoothened (ND2:SmoA1) alleles showed, that although granule cells expressing the ND2:SmoA1 transgene are present in the N-myc null cerebellum, no hyperproliferation or tumor formation was detected. Taken together, these findings provide in vivo evidence that N-myc acts downstream of Shh/Smo signaling during GNP proliferation and that N-myc is required for medulloblastoma genesis even in the presence of constitutively active signaling from the Shh pathway.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109, USA. berylh@u.washington.edu
authors.forename: Beryl A
authors.initials: BA
authors.lastname: Hatton
authors.forename: Paul S
authors.initials: PS
authors.lastname: Knoepfler
authors.forename: Anna Marie
authors.initials: AM
authors.lastname: Kenney
authors.forename: David H
authors.initials: DH
authors.lastname: Rowitch
authors.forename: Ignacio Moreno
authors.initials: IM
authors.lastname: de Alborán
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
authors.forename: Robert N
authors.initials: RN
authors.lastname: Eisenman
mesh_terms: D000818:Animals; D002455:Cell Division; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology; D002531:Cerebellum / Q000166:cytology* / Q000473:pathology; D002648:Child; D016259:Genes, myc; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016271:Proto-Oncogene Proteins c-myc / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D016271:Proto-Oncogene Proteins c-myc; C509239:SHH protein, human; C465570:Shh protein, mouse