The development of the basal ganglia and the formation of their connections are complex and poorly understood processes. The basal ganglia are integral to motor function, to cognitive and language development, and to social and emotional regulation. While some genes have been identified with roles in basal ganglia neuron specification, or in diseases of the basal ganglia, how these and other genes regulate the development of basal ganglia connectivity is not known. Further, the actual process of basal ganglia axon pathfinding during development has not been characterized. My hypothesis is that connectivity of the striatum and the mesodiencephalic dopaminergic (mesDA) neurons is controlled by the path- finding gene families of the robos, the s//fs, and the ephslephrins. My long-term objective is to characterize the development and genetic control of basal ganglia connectivity, using zebrafish (Danio rerio) as a model system. In order to explore the development of basal ganglia connections, this project has three specific aims:
Aim 1. Develop molecular and genetic markers to visualize striatal and mesodiencephalic dopaminergic (mesDA) neurons and their axons. I am using in situ gene markers and antibodies to label these nuclei. To study their pathfinding, I have generated novel enhancer lines specific for basal ganglia neurons, including dlx(mini):gfp and foxP2-enhancerA:egfp.
Aim 2. Characterize the normal axon pathfinding of the zebrafish striatum and mesDA neurons during development. I will use enhancergfp constructs and transgenic lines to describe the development of connectivity, and compare the pathfinding to the expression patterns of the ratios, slits, ephs, and ephrins.
Aim 3. Evaluate the role of robo, slit, and ephlephrin genes in striatal and mesDA neuron pathfinding. I will test the function and effects of different members of these gene families by using a combination of mutant fish lines and morpholinos. Clinical Significance: Our results will improve our understanding of the development of basal ganglia connectivity, which is affected in neurodevelopmental and neurodegenerative disorders. Summary: The work described here will be the first description of axon pathfinding of the basal ganglia, characterizing both the development of connectivity and its genetic basis. My results will include both descriptive elements of basal ganglia development, as well as analyses of the role of specific genes. This project consists of a well-structured career development plan, extensively supported with institutional resources and an internationally known mentor, to assist me with the transition during the K award to an independent tenure-track faculty position.
|Butterfield, Russell J; Stevenson, Tamara J; Xing, Lingyan et al. (2014) Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis. Neurology 82:1322-30|
|Sherwin, Catherine M T; Balch, Alfred; Campbell, Sarah C et al. (2014) Maternal magnesium sulphate exposure predicts neonatal magnesium blood concentrations. Basic Clin Pharmacol Toxicol 114:318-22|
|Doll, Elizabeth; Wilkes, Jacob; Cook, Lawrence J et al. (2014) Neonatal magnesium levels correlate with motor outcomes in premature infants: a long-term retrospective cohort study. Front Pediatr 2:120|
|Schweitzer, JÃ¶rn; LÃ¶hr, Heiko; Bonkowsky, Joshua L et al. (2013) Sim1a and Arnt2 contribute to hypothalamo-spinal axon guidance by regulating Robo2 activity via a Robo3-dependent mechanism. Development 140:93-106|
|Nelson, Clint; Mundorff, Michael B; Korgenski, E Kent et al. (2013) Determinants of health care use in a population-based leukodystrophyÂ cohort. J Pediatr 162:624-628.e1|
|Brimley, Cameron J; Lopez, Jonathan; van Haren, Keith et al. (2013) National variation in costs and mortality for leukodystrophy patients in US children's hospitals. Pediatr Neurol 49:156-162.e1|
|Lambert, Aaron M; Bonkowsky, Joshua L; Masino, Mark A (2012) The conserved dopaminergic diencephalospinal tract mediates vertebrate locomotor development in zebrafish larvae. J Neurosci 32:13488-500|
|Hoki, Robert; Bonkowsky, Joshua L; Minich, L LuAnn et al. (2012) Cardiac testing and outcomes in infants after an apparent life-threatening event. Arch Dis Child 97:1034-8|
|Xing, Lingyan; Hoshijima, Kazuyuki; Grunwald, David J et al. (2012) Zebrafish foxP2 zinc finger nuclease mutant has normal axon pathfinding. PLoS One 7:e43968|
|Lakhina, Vanisha; Marcaccio, Christina L; Shao, Xin et al. (2012) Netrin/DCC signaling guides olfactory sensory axons to their correct location in the olfactory bulb. J Neurosci 32:4440-56|
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