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 language | English (US) |
|---|---|
| Pages (from-to) | 8655-8661 |
| Number of pages | 7 |
| Journal | Cancer Research |
| Volume | 66 |
| Issue number | 17 |
| DOIs | |
| State | Published - Sep 1 2006 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
N-myc is an essential downstream effector of shh signaling during both normal and neoplastic cerebellar growth. / Hatton, Beryl A.; Knoepfler, Paul S; Kenney, Anna Marie; Rowitch, David H.; Moreno De Alborán, Ignacio; Olson, James M.; Eisenman, Robert N.
In: Cancer Research, Vol. 66, No. 17, 01.09.2006, p. 8655-8661.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - N-myc is an essential downstream effector of shh signaling during both normal and neoplastic cerebellar growth
AU - Hatton, Beryl A.
AU - Knoepfler, Paul S
AU - Kenney, Anna Marie
AU - Rowitch, David H.
AU - Moreno De Alborán, Ignacio
AU - Olson, James M.
AU - Eisenman, Robert N.
PY - 2006/9/1
Y1 - 2006/9/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=33749024194&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33749024194&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-06-1621
DO - 10.1158/0008-5472.CAN-06-1621
M3 - Article
C2 - 16951180
AN - SCOPUS:33749024194
VL - 66
SP - 8655
EP - 8661
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0099-7013
IS - 17
ER -