Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Genes & Dev. 22 (6): 722-727

Copyright © 2008 by Cold Spring Harbor Laboratory Press.


Post-transcriptional down-regulation of Atoh1/Math1 by bone morphogenic proteins suppresses medulloblastoma development

Haotian Zhao1,3, Olivier Ayrault1,3, Frederique Zindy1, Jee-Hae Kim2,, and Martine F. Roussel1,4

1 Departments of Genetics and Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, USA;
2 Laboratory of Developmental Neurobiology, Rockefeller University, New York, New York 10021, USA

Abstract: Bone morphogenic proteins 2 and 4 (BMP2 and BMP4) inhibit proliferation and induce differentiation of cerebellar granule neuron progenitors (GNPs) and primary GNP-like medulloblastoma (MB) cells. This occurs through rapid proteasome-mediated degradation of Math1 (Atoh1), a transcription factor expressed in proliferating GNPs. Ectopic expression of Atoh1, but not of Sonic hedgehog (Shh)-regulated Gli1 or Mycn, cancels these BMP-mediated effects and restores Shh-dependent proliferation of GNPs and MB cells in vitro and in vivo. Genes regulating the BMP signaling pathway are down-regulated in mouse MBs. Thus, BMPs are potent inhibitors of MB and should be considered as novel therapeutic agents.

Key Words: Medulloblastoma • Sonic hedgehog • bone morphogenic protein • Atoh1/Math1 • Mycn]

Received for publication November 21, 2007. Accepted for publication January 16, 2008.

3 These authors contributed equally to this work.

4 Corresponding author.

E-MAIL martine.roussel{at}; FAX (901) 495-2381.

Supplemental material is available at

Article is online at

Silencing of the miR-17~92 Cluster Family Inhibits Medulloblastoma Progression.
B. L. Murphy, S. Obad, L. Bihannic, O. Ayrault, F. Zindy, S. Kauppinen, and M. F. Roussel (2013)
Cancer Res. 73, 7068-7078
   Abstract »    Full Text »    PDF »
MicroRNA 22 Regulates Cell Cycle Length in Cerebellar Granular Neuron Precursors.
J. Berenguer, A. Herrera, L. Vuolo, B. Torroba, F. Llorens, L. Sumoy, and S. Pons (2013)
Mol. Cell. Biol. 33, 2706-2717
   Abstract »    Full Text »    PDF »
Candidate Pathways for Promoting Differentiation or Quiescence of Oligodendrocyte Progenitor-like Cells in Glioma.
J. D. Dougherty, E. I. Fomchenko, A. A. Akuffo, E. Schmidt, K. Y. Helmy, E. Bazzoli, C. W. Brennan, E. C. Holland, and A. Milosevic (2012)
Cancer Res. 72, 4856-4868
   Abstract »    Full Text »    PDF »
Canonical BMP7 activity is required for the generation of discrete neuronal populations in the dorsal spinal cord.
G. Le Dreau, L. Garcia-Campmany, M. A. Rabadan, T. Ferronha, S. Tozer, J. Briscoe, and E. Marti (2012)
Development 139, 259-268
   Abstract »    Full Text »    PDF »
High expression of BMP pathway genes distinguishes a subset of atypical teratoid/rhabdoid tumors associated with shorter survival.
D. K. Birks, A. M. Donson, P. R. Patel, C. Dunham, A. Muscat, E. M. Algar, D. M. Ashley, B. K. Kleinschmidt-DeMasters, R. Vibhakar, M. H. Handler, et al. (2011)
Neuro Oncology 13, 1296-1307
   Abstract »    Full Text »    PDF »
In Vivo Neuronal Subtype-Specific Targets of Atoh1 (Math1) in Dorsal Spinal Cord.
H. C. Lai, T. J. Klisch, R. Roberts, H. Y. Zoghbi, and J. E. Johnson (2011)
J. Neurosci. 31, 10859-10871
   Abstract »    Full Text »    PDF »
Cooperative activity of noggin and gremlin 1 in axial skeleton development.
D. A. Stafford, L. J. Brunet, M. K. Khokha, A. N. Economides, and R. M. Harland (2011)
Development 138, 1005-1014
   Abstract »    Full Text »    PDF »
Id Gene Regulation and Function in the Prosensory Domains of the Chicken Inner Ear: A Link between Bmp Signaling and Atoh1.
A. Kamaid, J. Neves, and F. Giraldez (2010)
J. Neurosci. 30, 11426-11434
   Abstract »    Full Text »    PDF »
Atoh1 Inhibits Neuronal Differentiation and Collaborates with Gli1 to Generate Medulloblastoma-Initiating Cells.
O. Ayrault, H. Zhao, F. Zindy, C. Qu, C. J. Sherr, and M. F. Roussel (2010)
Cancer Res. 70, 5618-5627
   Abstract »    Full Text »    PDF »
Deletion of Atoh1 Disrupts Sonic Hedgehog Signaling in the Developing Cerebellum and Prevents Medulloblastoma.
A. Flora, T. J. Klisch, G. Schuster, and H. Y. Zoghbi (2009)
Science 326, 1424-1427
   Abstract »    Full Text »    PDF »
Multiple Transcriptional Mechanisms Control Ptf1a Levels during Neural Development Including Autoregulation by the PTF1-J Complex.
D. M. Meredith, T. Masui, G. H. Swift, R. J. MacDonald, and J. E. Johnson (2009)
J. Neurosci. 29, 11139-11148
   Abstract »    Full Text »    PDF »
Multipotent CD15+ Cancer Stem Cells in Patched-1-Deficient Mouse Medulloblastoma.
R. J. Ward, L. Lee, K. Graham, T. Satkunendran, K. Yoshikawa, E. Ling, L. Harper, R. Austin, E. Nieuwenhuis, I. D. Clarke, et al. (2009)
Cancer Res. 69, 4682-4690
   Abstract »    Full Text »    PDF »
The miR-17~92 cluster collaborates with the Sonic Hedgehog pathway in medulloblastoma.
T. Uziel, F. V. Karginov, S. Xie, J. S. Parker, Y.-D. Wang, A. Gajjar, L. He, D. Ellison, R. J. Gilbertson, G. Hannon, et al. (2009)
PNAS 106, 2812-2817
   Abstract »    Full Text »    PDF »
N-myc alters the fate of preneoplastic cells in a mouse model of medulloblastoma.
J. D. Kessler, H. Hasegawa, S. N. Brun, B. A. Emmenegger, Z.-J. Yang, J. W. Dutton, F. Wang, and R. J. Wechsler-Reya (2009)
Genes & Dev. 23, 157-170
   Abstract »    Full Text »    PDF »
Two Tumor Suppressors, p27Kip1 and Patched-1, Collaborate to Prevent Medulloblastoma.
O. Ayrault, F. Zindy, J. Rehg, C. J. Sherr, and M. F. Roussel (2009)
Mol. Cancer Res. 7, 33-40
   Abstract »    Full Text »    PDF »
Just Say No to ATOH: How HIC1 Methylation Might Predispose Medulloblastoma to Lineage Addiction.
K. J. Briggs, C. G. Eberhart, and D. N. Watkins (2008)
Cancer Res. 68, 8654-8656
   Abstract »    Full Text »    PDF »
BMPs oppose Math1 in cerebellar development and in medulloblastoma.
M. R. Grimmer and W. A. Weiss (2008)
Genes & Dev. 22, 693-699
   Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882