Development of the neocortex and hippocampus is a
highly ordered process with a number of important steps. Cells must
be directed to the proper fate in the ventricular zone, must migrate
to the appropriate laminar location once born and must establish connectivity
with their targets. Many patients with epilepsy or congenital brain
malformations have morphologic abnormalities consistent with defects
in the control of cell fate, neuronal migration or axon guidance in
the developing telencephalon. Our research focuses on several distinct
aspects of the regulation of neuronal cell fate, migration and axon
guidance using the developing hippocampus as the model system. We
are using a broad array of embryologic and molecular genetic techniques
to understand these processes in the normal developing state as well
as in animals with developmental anomalies. We are studying these
issues by working on three separate but related topics.
1. Regulation of Patterning, Proliferation and Cell Fate in
the Developing and Adult Hippocampus
One focus of this project is on the role of Wnts and Wnt
receptors in regulating the development of the hippocampus. It is
known that a region adjacent to the developing hippocampus, called
the cortical hem, expresses a number of Wnt ligands. We have recently
shown that Wnt receptors and soluble Wnt inhibitors have specific
expression patterns in the developing hippocampus that makes it likely
that they play a role in receiving the signals emanating from the
cortical hem. Recent work on mice with mutations in Wnt signaling
molecules have pointed to a critical role in hippocampal development,
however, many questions remain unresolved.
2. Migration and Axon Guidance in the Developing Hippocampus
The laminated dentate gyrus and hippocampus are formed by specific
modes of cellular migration from the hippocampal ventricular zone.
The dentate gyrus in particular is unique in the mammalian nervous
system in that it is formed by a combined migration of mitotic precursor
cells and immature neurons. We are studying this question using
in vitro and in vivo assays of cell migration and the role of a
number of specific axon guidance and chemotactic migration inducing
molecules. Recently, we showed that the chemokine SDF-1 is a chemoattractant
that regulates the migration of granule cells from the ventricular
zone to the forming dentate gyrus.
The hippocampal formation has a highly stereotyped network of afferent
and efferent connections. Since the function of the hippocampus
in learning and memory is based on the integrity and function of
this circuitry, it is critical to gain an understanding of the developmental
processes that regulate the guidance of these axon fibers. We have
also begun to suspect that these developmental axon guidance mechanisms
also underlie some types of adult neural plasticity. Work in this
area in the lab focuses on the function of semaphorin ligands in
regulating the development and remodeling of hippocampal projections.
3. The Response of the Hippocampus and Dentate Gyrus to Injury During
Development
Developmental abnormalities in the dentate gyrus are associated
with a number of forms of epilepsy, learning disorders and mental
retardation. While there are many genetic mechanisms that are likely
to regulate these phenomena, it is probably more common that injury
early in life leads to these events. We are studying two forms of
such injury in collaboration with other laboratories. In one case
animals are treated with a teratogenic substance during embryonic
development that leads to well defined heterotopic neurons in the
developing hippocampal formation and cortex. In the other case,
animals are subjected to an episode of bacterial meningitis in the
early postnatal period. This insult is known to cause a specific
cellular response in the developing dentate gyrus. We are
in the process of studying the long-term functional and anatomic
consequences of this insult.
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Biomedical Sciences (BMS) Graduate Program
