Sonic hedgehog is a secreted signaling molecule that plays a critical role in regulating many aspects of development. In the cerebellum, Shh acts as a mitogen for neurons called granule cells. When these cells are exposed to Shh, they undergo a dramatic increase in proliferation. Conversely, when Shh signaling is blocked, there is a significant decrease in the number of granule cells generated. Most importantly, mutations that result in activation of Shh signaling are associated with cerebellar tumors in both humans and mice. These observations suggest that Shh signaling plays a central role in the etiology of medulloblastoma.

Our studies are directed at answering three major questions: (1) What are the molecular mechanisms by which Shh induces granule cell proliferation? (2) What are the signals that stop proliferation and allow granule cells to differentiate? And (3) How are proliferation and differentiation dysregulated in medulloblastoma? To address these questions we use a variety of techniques, including isolation and retroviral infection of primary neurons, analysis of gene expression using in situ hybridization and DNA microarrays, examination of protein expression by immunofluorescence microscopy, and analysis of tumor formation using transgenic and knockout mice. Using these approaches, we hope to gain insight into the mechanisms of normal development and contribute to the generation of more effective therapies for medulloblastoma.

Johnson CE, Huang YY, Parrish AB, Smith MI, Vaughn AE, Zhang Q, Wright KM, Van Dyke T, Wechsler-Reya RJ, Kornbluth S, Deshmukh M (2007) Differential Apaf-1 levels allow cytochrome c to induce apoptosis in brain tumors but not in normal neural tissues.  Proc Natl Acad Sci 104:20820-5. 

Emmenegger BA and Wechsler-Reya RJ (2008) Stem Cells and the Origin and Propagation of Brain Tumors. J. Child Neurol. 23:1172-8.

Yang ZJ, Ellis T, Markant SL, Read, TA, Kessler JD, Bourboulas M, Schüller U, Machold R, Fishell G, Rowitch, DH, Wainwright BJ and Wechsler-Reya RJ (2008) Medulloblastoma can be Initiated by Deletion of Patched in Lineage-Restricted Progenitors or Stem Cells. Cancer Cell. 14:135-45.

Kessler JD, Hasegawa H, Brun, SN, Emmenegger BA, Yang, ZJ, Dutton JW, Wang F and Wechsler-Reya RJ (2009) N-myc Alters the Fate of Pre-Neoplastic Cells in a Mouse Model of Medulloblastoma. Genes & Dev. 23:157-170.

Read TA, Fogarty MP, Markant SL, McLendon RE, Wei Z, Ellison DW, Febbo PG and Wechsler-Reya RJ (2009) Identification of CD15 as a Marker for Tumor-Propagating Cells in a Mouse Model of Medulloblastoma. Cancer Cell. 15:135-47.

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Oliver, T.G., Read, T.A., Kessler, J.D., Mehmeti, A., Wells, J.F., Huynh, T.T., Lin, S.M. and Wechsler-Reya, R.J. (2005) Loss of patched and disruption of granule cell development in a pre-neoplastic stage of medulloblastoma. Development 132:2425-39

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