Intercellular
interactions in the developing nervous system; neuron-glia
relationships; functional organization of olfactory systems
Research
in my laboratory focuses on the development and functional
organization of the olfactory system, studied in convenient
model organisms, the moth Manduca sexta and, very recently, the fruitfly Drosophila melanogaster. Several different lines of investigation have led us to focus much of our attention
on roles for glial cells in development and in mature function.
Development
of the olfactory pathway. Over the years, our research has been aimed primarily at elucidating key intercellular
interactions during development of the olfactory system.
My coworkers and I have been especially interested in the
mechanisms underlying the wide-spread phenomenon that sensory
neurons guide many aspects of development in their target
areas in the brain. Using the olfactory system of Manduca, we found in 1987 that glial cells must be present in order for the axons of
olfactory receptor neurons, whose cell bodies are located
in the antenna, to induce the formation of synaptic glomeruli
in the antennal lobes of the brain.
Much
of our work since then has built on the hypothesis that glial
cells act as intermediaries in the developmental influence
that olfactory axons exert upon their targets - i.e. that glial
cells, which are induced by axons to surround developing glomeruli,
form a necessary scaffold within which receptor neurons and
target neurons subsequently differentiate their glomerular
arbors. We have discovered that neuronal activity is not necessary
for the formation of a glomerular architecture, so we are focusing
our attention on cell-surface and extracellular signaling molecules,
such as fasciclin II, tenascin, and nitric oxide, that could
be involved.
We
also are interested in another issue, that of axon guidance,
as we seek to understand how olfactory receptor axons sort
into glomerulus-specific bundles and then find their correct
glomerular targets in the antennal lobe. We have discovered
a glia-rich "sorting zone" in the antennal nerve (Fig. 1), and, using methods that deplete the developing
system of glial cells, we have found that those glial cells
must be present for the axons to sort properly. We use in vitro
methods and live-cell video microscopy to explore in detail
the interactions between the growth cones of olfactory receptor
axons and glia from the sorting zone (Fig. 2) and from other
parts of the olfactory pathway.
In
collaborative experiments with the groups of Drs. John Hildebrand
and Alan Nighorn, we have extended these studies to include
examination of how male-specific olfactory receptor axons find
their unique targets in the antennal lobe, taking particular
advantage of the ability to transplant developing antennae
between sexes. Further, in collaboration with investigators
at other universities, we are exploring how adhesion molecules,
present on subsets of olfactory receptor axons, help to guide
the axons to their specific targets; we are particularly interested
in whether expression of adhesion molecules is influenced by
neuron-glia interactions.
Recently,
in collaboration with Dr. Konrad Zinsmaier, we have begun to
use the simpler olfactory system of Drosophila for molecular genetic investigations of neuron-glia interactions that are similar
to those we have explored in Manduca.
In
the long run, we hope to understand the intercellular interactions
between developing receptor neurons, their target neurons in
the brain, and glial cells at a molecular level. We expect
that the knowledge we gain will offer insights into intercellular
influences in less accessible developing mammalian sensory
systems.
Function
of olfactory glomeruli. A separate line of experiments addresses the functional architecture of olfactory
glomeruli. Our long-standing collaboration with Dr. John
Hildebrand has revealed aspects of the synaptic organization
of neurons in the mature antennal lobe of Manduca, and a collaboration with Drs. Ed Arbas and Mark Willis revealed that glomerular
architecture is not necessary for odor-modulated flight behavior.
In
collaboration with Drs. Timothy Secomb and Anita Goriely, we
have developed mathematical models, based on data from the Manduca antennal system, of ionic diffusion within mature glomeruli and across the glial
boundaries between glomeruli. From these models, we learned
that the glial borders of glomeruli are likely to limit the
diffusion of potassium ions sufficiently to have a substantial
impact on electrical activity within activated glomeruli. Again,
the goal is to use the experimental advantages and our detailed
knowledge of the moth antennal system to shed light on the
organization of olfactory systems in general. |
