| Normal development requires a delicate balance between 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. Our research focuses on the molecular mechanisms
that regulate cell growth and tumorigenesis in the nervous system.
In particular, we study the role of the Sonic hedgehog (Shh) signaling
pathway in the development of the cerebellum and in the genesis of
a brain tumor called 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 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. |
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