During neural development, neuronal growth cones navigate long distances to their target regions. The mechanisms and molecules that guide growing neurons to their final destinations are the central focus of our laboratory research. We have chosen to study this issue in the developing avian peripheral nervous system because of a rich literature detailing the tissue interactions that influence the pathfinding of motor axons. Our long-term goal is to dissect apart the key molecular mechanisms that influence motor axons as they extend from the ventral neural tube to their muscle targets. The proposed studies focus on the patterning of motor axons in a portion of their pathway, the somitic mesoderm. We will take loss- of-function and gain-or-function approaches to examine the roles of two sets of candidate guidance cues: 1) the Eph family of receptor tyrosine kinases (RTKs) and their ligands, the ephrins, and 2) two glycoproteins that bind the lectin peanut agglutinin.
The specific aims of our studies are as follows: 1) Analyze the effects of blocking Eph RTK-ligand interaction on the segmental patterning of motor axons; 2) Examine effects of ectopic expression of ephrin-B1 on axon outgrowth in vivo; 3) Analyze the function of PNA-binding molecules in patterning motor axons. We will take advantage of a novel whole embryo explant system where we can perturb guidance cues and examine the subsequent effects on motor axons using time- lapse videomicroscopy. Avian-specific retroviruses will be used to misexpress ephrins in ectopic regions, a gain-of-function approach to analyze the roles of these guidance cues in axon pathfinding. The results of these studies will provide critical insights about the positive and negative factors that sculpt patterns of neural architecture during development and may have important implications for neural regeneration in response to injury or disease.
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