N-myc is an essential downstream effector of Shh signaling during both normal and neoplastic cerebellar growth.
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.
Hatton
Beryl A
BA
Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA 98109, USA. berylh@u.washington.edu
Knoepfler
Paul S
PS
Kenney
Anna Marie
AM
Rowitch
David H
DH
de Alborán
Ignacio Moreno
IM
Olson
James M
JM
Eisenman
Robert N
RN
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
D053823:Hedgehog Proteins; D016271:Proto-Oncogene Proteins c-myc; C509239:SHH protein, human; C465570:Shh protein, mouse