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 potent 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. Importantly, mutations that result in activation
of Shh signaling are associated with cerebellar tumors
(medulloblastomas) in both mice and humans. 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 that
control 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.
