GENETIC ANALYSIS OF THE FUNCTION OF EPH RECEPTORS AND LIGANDS

The large family of Eph receptor tyrosine kinases is responsible for a unique array of cellular functions including cell migration, cell segregation, and axon guidance. We have employed the anatomically segregated and genetically facile olfactory sensory system as a model to understand the molecular mechanisms of ephrin-A-mediated cell signaling. The development of genetic approaches to visualize axons from sensory neurons as they project to precise locations in the brain has permitted us to dissect these complex, yet precise neuronal migrations. Our data suggest that ephrin-As on the growing sensory axon act in concert with odorant receptors as guidance molecules responsible for the generation of a precise topographic map. This immediately poses a series of interesting questions that specifically address the mechanism by which ephrin-As control sensory axon migration and more generally may define the mechanisms of ephrin-A signaling in other cells. What is the mechanism by which ephrin-A, a surface molecule without a transmembrane domain, transduces extracellular information into meaningful intracellular events? What are the downstream pathways through which ephrin-A signals to guide axons to discrete topographic locations? Finally, what is the nature of the guidance molecules recognized by both ephrin-A and the odorant receptors to allow them an instructive role in targeting like axons to precise loci in the brain?