This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hatton, B. A. Articles by Eisenman, R. N. Search for Related Content PubMed PubMed Citation Articles by Hatton, B. A. Articles by Eisenman, R. N.

N-myc Is an Essential Downstream Effector of Shh Signaling during both Normal and Neoplastic Cerebellar Growth

¹ Clinical Research Division and ² Division of Basic Sciences, Fred Hutchinson Cancer Research Center; ³ Graduate Program in Molecular and Cellular Biology, University of Washington; ⁴ Division of Pediatric Oncology, University of Washington/Children's Hospital, Seattle, Washington; ⁵ Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York; ⁶ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; and ⁷ Department of Immunology and Oncology, National Center for Biotechnology, Madrid, Spain

Requests for reprints: Beryl A. Hatton, Graduate Program in Molecullar and Cell Biology, University of Washington/Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mailstop D4-100, P. O. Box 19024, Seattle, WA 98109. E-mail: berylh{at}u.washington.edu.

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. (Cancer Res 2006; 66(17): 8655-61)

This article has been cited by other articles:

				R. Alvarez-Rodriguez and S. Pons Expression of the proneural gene encoding Mash1 suppresses MYCN mitotic activity J. Cell Sci., March 1, 2009; 122(5): 595 - 599. [Abstract] [Full Text] [PDF]

				P.-O. Frappart, Y. Lee, H. R. Russell, N. Chalhoub, Y.-D. Wang, K. E. Orii, J. Zhao, N. Kondo, S. J. Baker, and P. J. McKinnon Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency PNAS, February 10, 2009; 106(6): 1880 - 1885. [Abstract] [Full Text] [PDF]

				M. Nagao, K. Campbell, K. Burns, C.-Y. Kuan, A. Trumpp, and M. Nakafuku Coordinated control of self-renewal and differentiation of neural stem cells by Myc and the p19ARF-p53 pathway J. Cell Biol., December 29, 2008; 183(7): 1243 - 1257. [Abstract] [Full Text] [PDF]

				M. Varjosalo and J. Taipale Hedgehog: functions and mechanisms Genes & Dev., September 15, 2008; 22(18): 2454 - 2472. [Abstract] [Full Text] [PDF]

				X. Fan and C. G. Eberhart Medulloblastoma Stem Cells J. Clin. Oncol., June 10, 2008; 26(17): 2821 - 2827. [Abstract] [Full Text] [PDF]

				B. A. Hatton, E. H. Villavicencio, K. D. Tsuchiya, J. I. Pritchard, S. Ditzler, B. Pullar, S. Hansen, S. E. Knoblaugh, D. Lee, C. G. Eberhart, et al. The Smo/Smo Model: Hedgehog-Induced Medulloblastoma with 90% Incidence and Leptomeningeal Spread Cancer Res., March 15, 2008; 68(6): 1768 - 1776. [Abstract] [Full Text] [PDF]

				M. R. Grimmer and W. A. Weiss BMPs oppose Math1 in cerebellar development and in medulloblastoma Genes & Dev., March 15, 2008; 22(6): 693 - 699. [Full Text] [PDF]

				R. A.P. Martins, F. Zindy, S. Donovan, J. Zhang, S. Pounds, A. Wey, P. S. Knoepfler, R. N. Eisenman, M. F. Roussel, and M. A. Dyer N-myc coordinates retinal growth with eye size during mouse development Genes & Dev., January 15, 2008; 22(2): 179 - 193. [Abstract] [Full Text] [PDF]

				F. Zindy, T. Uziel, O. Ayrault, C. Calabrese, M. Valentine, J. E. Rehg, R. J. Gilbertson, C. J. Sherr, and M. F. Roussel Genetic Alterations in Mouse Medulloblastomas and Generation of Tumors De novo from Primary Cerebellar Granule Neuron Precursors Cancer Res., March 15, 2007; 67(6): 2676 - 2684. [Abstract] [Full Text] [PDF]