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Distinct roles for fibroblast growth factor signaling in cerebellar development and medulloblastoma

Oncogene volume 32, pages 4181–4188 (2013)Cite this article

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Abstract

Cerebellar granule neurons are the most abundant neurons in the brain, and a critical element of the circuitry that controls motor coordination and learning. In addition, granule neuron precursors (GNPs) are thought to represent cells of origin for medulloblastoma, the most common malignant brain tumor in children. Thus, understanding the signals that control the growth and differentiation of these cells has important implications for neurobiology and neurooncology. Our previous studies have shown that proliferation of GNPs is regulated by Sonic hedgehog (Shh), and that aberrant activation of the Shh pathway can lead to medulloblastoma. Moreover, we have demonstrated that Shh-dependent proliferation of GNPs and medulloblastoma cells can be blocked by basic fibroblast growth factor (bFGF). But while the mitogenic effects of Shh signaling have been confirmed in vivo, the inhibitory effects of bFGF have primarily been studied in culture. Here, we demonstrate that mice lacking FGF signaling in GNPs exhibit no discernable changes in GNP proliferation or differentiation. In contrast, activation of FGF signaling has a potent effect on tumor growth: treatment of medulloblastoma cells with bFGF prevents them from forming tumors following transplantation, and inoculation of tumor-bearing mice with bFGF markedly inhibits tumor growth in vivo. These results suggest that activators of FGF signaling may be useful for targeting medulloblastoma and other Shh-dependent tumors.

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Acknowledgements

We thank Marcie Kritzik for help with the paper, Kerry Dorr for contributions to the early stages of this work, Albert Basson for helpful discussions, Chuxia Deng, David Ornitz and James Olson for providing mice, Matthias Lauth and Rune Toftgard for Sufu−/− MEFs, Sam Johnson for help with microscopy, Amanda Conway for help with western blotting, and Mike Cook and Beth Harvat for help with flow cytometry. This work was funded by grant number MH67916 from the National Institute of Mental Health, by funds from the Pediatric Brain Tumor Foundation of the US, and by a Leadership Award (LA1–01747) from the California Institute for Regenerative Medicine.

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Authors and Affiliations

  1. Department of Pharmacology & Cancer Biology and Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA

    B A Emmenegger, S L Markant, S N Brun & R J Wechsler-Reya

  2. Children’s National Medical Center, Washington, DC, USA

    E I Hwang

  3. Tumor Development Program, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA

    C Moore, S L Markant, S N Brun & R J Wechsler-Reya

  4. College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA

    J W Dutton

  5. Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, USA

    T-A Read

  6. Department of Genetics, University of North Carolina Chapel Hill, NC, USA

    M P Fogarty

  7. Department of Pediatrics, University of California San Diego, San Diego, CA, USA

    A R Singh & D L Durden

  8. Center for Cancer & Stem Cell Biology, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USA

    C Yang & W L McKeehan

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  1. B A Emmenegger
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Emmenegger, B., Hwang, E., Moore, C. et al. Distinct roles for fibroblast growth factor signaling in cerebellar development and medulloblastoma. Oncogene 32, 4181–4188 (2013). https://doi.org/10.1038/onc.2012.440

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