N-myc is an essential downstream effector of shh signaling during both normal and neoplastic cerebellar growth

Beryl A. Hatton, Paul S Knoepfler, Anna Marie Kenney, David H. Rowitch, Ignacio Moreno De Alborán, James M. Olson, Robert N. Eisenman

Research output: Contribution to journalArticle

116 Scopus citations

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-mycFl/Fl and c-mycFl/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.

Original languageEnglish (US)
Pages (from-to)8655-8661
Number of pages7
JournalCancer Research
Volume66
Issue number17
DOIs
StatePublished - Sep 1 2006
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Hatton, B. A., Knoepfler, P. S., Kenney, A. M., Rowitch, D. H., Moreno De Alborán, I., Olson, J. M., & Eisenman, R. N. (2006). N-myc is an essential downstream effector of shh signaling during both normal and neoplastic cerebellar growth. Cancer Research, 66(17), 8655-8661. https://doi.org/10.1158/0008-5472.CAN-06-1621