Cellular and molecular analysis of axon development in zebrafish

Brain wiring is critical for normal brain function, and brain connection defects have been described in many neurodevelopmental disorders. Accurate central nervous system connectivity relies on precise axon navigation. The cellular and molecular mechanisms governing axon guidance during development are important but not well understood. In this dissertation, I utilize zebrafish, a powerful vertebrate model in developmental and genetic studies, to determine the molecular mechanisms regulating axon guidance in vivo. We specifically determine the role of the two molecules FoxP2 and serotonin (5-HT) in axon guidance. We demonstrate that FoxP2, a forkhead-domain transcription factor, is not required for axon guidance, but it reduces the expression levels of a synaptic protein Cntnap2. We also establish that 5-HT and its receptor Htr2a are important for axon guidance. The regulation of 5-HT on axon guidance is mediated by the tyrosine kinase Ephrinb2a. Moreover, we discover that axon guidance defects induced by environmental hypoxia can be rescued by serotonin reuptake inhibitor fluoxetine. I have also developed and implemented a PCR-based high resolution melting analysis (HRMA) for large-scale genotype screening and characterization of genes involved in axon development. Taken together, this work identifies a novel mechanism involved in central nervous system connectivity, and indicates raphe 5-HT neurons act as a sensor to alterations in the developmental environment.