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.
