Sonic Hedgehog Signaling in Neural Development and Tumorigenesis
Normal development requires a delicate balance between cellular proliferation, differentiation, and death. When these processes become dysregulated, a cell that would normally differentiate or die may divide uncontrollably, and a tumor may result. Dr. Robert Wechsler-Reya’s research focuses on the molecular mechanisms that regulate cell growth and tumorigenesis in the nervous system. In particular, Wechsler-Reya and colleagues study the role of the Sonic hedgehog (Shh) signaling pathway in the development of the cerebellum and in the genesis of medulloblastoma.
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 granule cell precursors (GCPs) 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 in a gene called patched, which result in activation of Shh signaling, are associated with cerebellar tumors (medulloblastomas) in both humans and mice. These observations suggest that Shh signaling plays a central role in the etiology of medulloblastoma.
Wechsler-Reya’s studies are directed at answering three major questions:
- What are the molecular mechanisms by which Shh induces granule cell proliferation,
- What are the signals that stop proliferation and allow granule cells to differentiate, and
- How are proliferation and differentiation dysregulated in medulloblastoma?
To address these questions, researchers 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, the investigators hope to gain insight into the mechanisms of normal development and contribute to the generation of more effective therapies for medulloblastoma.