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.

SC-INBRE Research

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 [12], 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.