CIUSSS Capitale nationale logo

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

Publication Type:

Journal Article

Source:

Dev Cell, Volume 31, Issue 1, p.34-47 (2014)

Keywords:

Animals, Cell Proliferation, Cerebellar Neoplasms, Cyclin D1, DNA Damage, Hedgehog Proteins, Humans, Immunoglobulin G, Medulloblastoma, Mice, Mice, Inbred C57BL, Neural Stem Cells, Patched Receptors, Patched-1 Receptor, Receptors, Cell Surface, Signal Transduction, Up-Regulation

Abstract:

<p>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.</p>

Financement / Soutien / Partenaires

logo FRQ-S logo ctrn logo fci logo cihr irsc logo nserc logo MESISentinelle nord