Semaphorin3/Neuropilin Binding Specificities Are Stable In The Evolution And Their Function In The Development Of The Olfactory System

The convergence of olfactory sensory axons onto topographically fixed,odorant receptor specific glomeruli in the olfactory bulb(OB)is a complex biological problem.Early in development,axons from olfactory sensory neurons(OSNs)extend into the OB where they innervate distinct neuropilar structures called protoglomeruli.Protoglomeruli subsequently segregate into mature glomeruli.The zebrafish is an excellent system in which to study early protoglomerular targeting.At 72 hours post-fertilization,the zebrafish OB contains 12 easily identifiable protoglomerulis.The objective of this thesis work was to identify axon guidance cues and receptors that direct olfactory sensory axons to their protoglomerular targets.The last common ancestors of terrestrial vertebrates and teleost fishes are thought to have diverged approximately 400 million years ago.We examined the functional conservation of a key family of axonal guidance cues and signaling molecules,the class Ⅲ semaphorins,during this time period.With only a few exceptions,othologous mouse and zebrafish semaphorins prefer to bind to the same(neuropilin)binding partners.Duplicated semaphorins,thought to have diverged near the beginning of the teleost lineage,all had nearly identical binding preferences.These findings suggest a very high conservation of functional identity ithin this important class of signaling molecules over an extremely long time period.They are consistent with a model of semaphorin specialization that is more dependent upon their acquiring unique developmental expression patterns than assuming new specialized biochemical properties.Additional class 3 semaphorins,not previously implicated in olfactory development,are expressed in the olfactory system during development.Mutations in nrpla,nrplb and nrp2b result in sema3D independent targeting errors.These findings suggest that many class 3 semaphorins cooperate in protoglomerular map formation.These studies highlight the utility of the zebrafish as a model for the study of early olfactory axon guidance,and provide the foundation for the future study of semaphorin/neuropilin signaling in the developing olfactory system.