| Neuron navigator 2 (Nav2) was previously identified in our lab using a subtractive hybridization library prepared from all- trans retinoic acid (atRA) treated and untreated SH-SY5Y human neuroblastoma cells; these cells exhibit neurite outgrowth when exposed to atRA. Nav2 is the human homologue of C. elegans unc-53, which is required for normal mechanosensory neuron elongation and branching in C.elegans. In this dissertation, the role of Nav2 in the nervous system is characterized through mutational analysis and knockdown studies in cell culture, rescue experiments in the unc-53 C. elegans mutant and characterization of unc-53h2 (Nav2) hypomorphic mutant mice.;We show that Nav2 is an ortholog of unc-53. Transgene expression of human NAV2 under a mechanosensory neuron promoter in C. elegans unc-53(e404) produces a nearly complete rescue of the posterior lateral microtubule defect. In cell culture, we also show that Nav2 expression is similar to that of neurofilament and is required for atRA-induced neurite outgrowth.;Studies in the Nav2 hypomorphic mutant mouse further elucidate the functions of this gene in vivo. Hypomorphs display a variety of behavioral abnormalities, including ataxia, as well as decreased brain and body weight, a decreased survival rate at birth and defects in developing nervous tissues, including cranial nerves, eye and cerebellum. These mutants exhibit morphological and functional defects of cranial nerves IX and X, which regulate the baroreceptor reflex. Nav2 hypomorphic mice exhibit defects in structures that form early (embryonic day 8.5) and later (embryonic day 12.5 and after) in eye development suggesting a possible role for Nav2 at both of these times. Nav2 is integral for proper external granule layer (EGL) migration and ultimately foliation of the developing cerebellum. The foliation defects are 100% penetrant in the hypomorphic mice, proving that Nav2 is critical for normal cerebellum development.;As a whole, this work demonstrates an important functional role for Nav2 in axonal elongation and nervous system development. |
