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Dev Cell. 2014 Oct 13;31(1):34-47. doi: 10.1016/j.devcel.2014.08.010. Epub 2014 Sep 25.

The Shh receptor Boc promotes progression of early medulloblastoma to advanced tumors.

Author information

1
Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal (IRCM), 110 Pine Avenue West, Montreal QC H2W 1R7, Canada; Department of Medicine, University of Montreal, 2900 Boulevard Edouard-Montpetit, Montréal QC H3T 1J4, Canada.
2
Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal (IRCM), 110 Pine Avenue West, Montreal QC H2W 1R7, Canada; Integrated Program in Neuroscience, McGill University, 845 Sherbrooke Street West, Montréal QC H3A 0G4, Canada.
3
The Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto ON M5G 1L7, Canada.
4
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany; Department of Neuropathology, University of Heidelberg, 69120 Heidelberg, Germany.
5
Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal (IRCM), 110 Pine Avenue West, Montreal QC H2W 1R7, Canada.
6
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany.
7
Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69121 Heidelberg, Germany; Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, University of Heidelberg, 69120 Heidelberg, Germany.
8
Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal (IRCM), 110 Pine Avenue West, Montreal QC H2W 1R7, Canada; Department of Medicine, University of Montreal, 2900 Boulevard Edouard-Montpetit, Montréal QC H3T 1J4, Canada; Integrated Program in Neuroscience, McGill University, 845 Sherbrooke Street West, Montréal QC H3A 0G4, Canada; Department of Anatomy and Cell Biology, Department of Biology, and Division of Experimental Medicine, McGill University, 845 Sherbrooke Street West, Montréal QC H3A 0G4, Canada. Electronic address: frederic.charron@ircm.qc.ca.

Abstract

During cerebellar development, Sonic hedgehog (Shh) signaling drives the proliferation of granule cell precursors (GCPs). Aberrant activation of Shh signaling causes overproliferation of GCPs, leading to medulloblastoma. Although the Shh-binding protein Boc associates with the Shh receptor Ptch1 to mediate Shh signaling, whether Boc plays a role in medulloblastoma is unknown. Here, we show that BOC is upregulated in medulloblastomas and induces GCP proliferation. Conversely, Boc inactivation reduces proliferation and progression of early medulloblastomas to advanced tumors. Mechanistically, we find that Boc, through elevated Shh signaling, promotes high levels of DNA damage, an effect mediated by CyclinD1. High DNA damage in the presence of Boc increases the incidence of Ptch1 loss of heterozygosity, an important event in the progression from early to advanced medulloblastoma. Together, our results indicate that DNA damage promoted by Boc leads to the demise of its own coreceptor, Ptch1, and consequently medulloblastoma progression.

PMID:
25263791
DOI:
10.1016/j.devcel.2014.08.010
[Indexed for MEDLINE]
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