I am interested in the development of the nervous system. During the process of development, the fertilized egg, a single cell, divides and differentiates into all the tissues and organs of the developing organism. From a developmental perspective, this is extremely amazing in the nervous system, as the nervous system needs to form from nothing (de novo) and then connect itself up into a highly intricate and precisely functioning system. This is accomplished throughout the process of development. Nerve cells, known as neurons, are derived from stem cells which differentiate. After the nerve cells are formed, they then send out long processes known as axons. These axons must navigate through a variety of intervening tissues to connect up to the correct targets where they form connections, known as synapses. I am interested in the question of how do these axons know where to go and where to connect? Specifically, I am interested in what the molecular cues in the tissue environment are that these axons use to determine the correct pathway and target and how these cues work to guide the axons.
My research interest is in the development
of the nervous system. During development, neurons send out their
axons which must navigate through intervening tissue in order
to innervate the correct target in a self-wring process. The
fundamental question I am interested in is how axons know where
to go and how they get there - the problem of axon guidance.
I am specifically studying the visual system. During early development,
the optic nerve forms when specific neurons in the eye, the retinal
ganglion cells (RGCs), send out axons, which are tipped by a
motile structure, the growth cone, that navigate through the
tissues and then find and connect with their target, which is
the tectum in birds (or the LGN and superior colliculus in mammals).
Thus, the research question I am interested in becomes what molecular
signals guide these RGC axons to their target?
Over the last 30 years, significant progress has been made in
identifying some of the molecules that are involved in RGC axon
guidance as well as their receptors in the RGC growth cones [1,2]. Most of the work so far has focused
on proteins as axon guidance molecules. However, there is another
class of biological molecules, lysophospholipids, especially
lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P),
which are just beginning to be recognized as important molecules
for signaling cells in various biological processes. Lysophospholipids
have been shown to signal cells with various physiological effects
by binding to and activating specific G protein-coupled receptors
(GPCRs), leading to intracellular signaling events [3-7].
In addition, there have been indications that lysophospholipids
are involved in aspects of the development of the nervous system
[3,8], including experimental evidence
that LPA inhibits the neurites of neuronal cell lines in culture
[9-11]. Furthermore, I have shown
that LPA causes growth cone collapse of RGCs in vitro, both from
chick and mouse , leading to the
hypothesis that LPA may be an important axon guidance molecule
for RGCs by acting in an inhibitory manner to direct RGC growth
cones away from LPA-secreting tissues.
In my laboratory, we are investigating this
hypothesis in the developing chicken visual system, which is
a well-established system that has a well-defined pathway which
retinal ganglion cell (RGC) axons navigate with various guidance
decisions, from initial growth in the retina to various choice
points along the path to final innervation of the optic tectum
in a crude topographic map [1,2,13].
We use a variety of cellular and molecular approaches to test
various aspects of this hypothesis, both in cell culture and
also in the embryo.