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

Copyright © 2008 by Cold Spring Harbor Laboratory Press.

RESEARCH COMMUNICATION

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}stjude.org; FAX (901) 495-2381.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1636408.

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