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

• Type of Material: Article
• Authors: Brian A. Emmenegger, Duke University; Eugene I. Hwang, Children's National Medical Center; Colin Moore, Sanford-Burnham Medical Research Institute; Shirley L. Markant, Duke University; Sonja N. Brun, Duke University; John W. Dutton, North Carolina State University; Tracy Read, Emory University; Marie P. Fogarty, University of North Carolina; Alok R. Singh, University of California, San Diego; Donald L. Durden, University of California, San Diego; Chaofeng Yang, Texas A&M Health Sciences Center; Wallace L. McKeehan, Texas A&M Health Sciences Center; Robert J. Wechsler-Reya, Duke University
• Language: English
• Date: 2013-08-29
• Publisher: Springer Nature [academic journals on nature.com]: Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 Macmillan Publishers Limited All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/onc.2012.440
• Title of Journal or Parent Work: Oncogene
• ISSN: 0950-9232
• Volume: 32
• Issue: 35
• Start Page: 4181
• End Page: 4188
• Grant/Funding Information: 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.
• Keywords: Cell Biology; Science & Technology; Biochemistry & Molecular Biology; CELL-PROLIFERATION; Genetics & Heredity; IDENTIFICATION; sonic hedgehog; medulloblastoma; PRECURSORS; STEM-CELLS; Oncology; EXPRESSION; SUPPRESSOR; DIFFERENTIATION; granule; PROGRESSION; HEDGEHOG PATHWAY INHIBITOR; FACTOR RECEPTOR; basic FGF; cerebellum; Life Sciences & Biomedicine
• Research Categories: Biology, Neuroscience; Health Sciences, Oncology; Biology, Molecular

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.