Principles of semaphorin signaling: The role of plexin receptors and small GTPases in nervous system development

Understanding how the nervous system organizes during early development is of great interest and significance to the scientific and medical communities. While large families of molecules are known to play roles in guiding developing neurons, understanding the specific relationships between such ligands, their receptors, and downstream signaling molecules is still being examined. It is especially interesting to conceptualize the immense diversity of these molecules in guiding the highly variable processes that must occur during the early development of the nervous system. The following studies investigate the signaling of the semaphorin family of guidance molecules during the development of the peripheral and central nervous systems, in sympathetic and cortical neurons, respectively. A background is provided that discusses the known biological roles of semaphorins, and the receptors and downstream molecules that have been implicated in such activities. As semaphorins are most well-known as molecules that guide extending axons, we initially examine this process in developing sympathetic axons and specifically study the interactions between semaphorins and their plexin receptors. Additionally, we investigate whether these same interactions are also required to guide the migration of sympathetic precursors during development. To determine the receptors involved in sympathetic guidance and migration, we describe the development of mutant mice lacking single or multiple semaphorin receptors. In addition to the diversity in ligand-receptor interactions that occurs during nervous system development, even more complexity is conveyed through receptors signaling to downstream molecules. Modulating the activity of intracellular molecules may also direct neuronal development downstream of semaphorin receptors. As such, we determine how the activity of a single cytoplasmic molecule, the Rit1 small GTPase, may guide developing neurons. We also study how semaphorin signaling through plexins may alter the activity of Rit1 and therefore guide neuronal development. This research provides evidence that interactions between ligands, receptors, and their downstream cytoplasmic molecules all add to the immense complexity required for the proper formation of the nervous system.