The goal of this proposal is to understand how developmental mechanisms contribute to neural circuits controlling animal behaviors. The simple neuroanatomy and repertoire of stereotyped locomotor behaviors of larval zebrafish provide an ideal model to study the contribution of developmental genes to the formation and function of neural circuits underlying defined motor behaviors. In this proposal, I will use the zebrafish 'space cadet'mutant as a tool to investigate mechanisms of axon guidance in the context of forming neural circuits that modulate a particular behavior called the """"""""escape response"""""""". Larval zebrafish perform this maneuver in response to tactile or acoustic stimuli. Mutations in the space cadet gene result in an errant execution of the escape response, caused by a guidance defect of a small subset of specialized commissural hindbrain neurons, called the spiral fiber neurons, which are part of a highly conserved """"""""brainstem escape network"""""""" of neurons that control motor behaviors. In addition, retinal ganglion cell orientation and pathfinding defects within the retina suggest that space cadet plays a critical role in intraretinal pathfinding, a process that is poorly understood. In this proposal, I first will use recombination mapping, DMA sequence analysis, gene expression patterns, and gene misexpression techniques to determine the molecular identity of the space cadet gene to better understand its function in the context of molecular signaling pathways. Second, I will use in vivo timelapse imaging of retinal ganglion cell and spiral fiber axons in wild-type and space cadet mutant embryos to provide insight into the role(s) space cadet plays in mediating neuronal growth cone guidance in vivo. Finally, I will determine whether spiral fiber neurons and their downstream neuronal synaptic partners are required to mediate specific turning behaviors in response to environmental stimuli. Together, these experiments will provide insights into the functional implication of vertebrate axon guidance on animal behavior. My proposed experiments and analyses will result in novel information essential for understanding mechanisms of axon pathfinding and the control of motor behaviors by neural circuits. Moreover, the results from these studies will also provide a foundation on which to address the mechanisms underlying human congenital disorders causing visual and locomotor impairment.

National Institute of Health (NIH)
National Eye Institute (NEI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F03A-F (20))
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Steinmetz, Michael A
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University of Pennsylvania
Anatomy/Cell Biology
Schools of Medicine
United States
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Wolman, Marc A; Jain, Roshan A; Marsden, Kurt C et al. (2015) A genome-wide screen identifies PAPP-AA-mediated IGFR signaling as a novel regulator of habituation learning. Neuron 85:1200-11
Fischer, Audrey; Wolman, Marc; Granato, Michael et al. (2015) Carbamate nerve agent prophylatics exhibit distinct toxicological effects in the zebrafish embryo model. Neurotoxicol Teratol 50:1-10
Gyda, Michael; Wolman, Marc; Lorent, Kristin et al. (2012) The tumor suppressor gene retinoblastoma-1 is required for retinotectal development and visual function in zebrafish. PLoS Genet 8:e1003106
Hao, Le T; Wolman, Marc; Granato, Michael et al. (2012) Survival motor neuron affects plastin 3 protein levels leading to motor defects. J Neurosci 32:5074-84
Wolman, Marc A; Jain, Roshan A; Liss, Laura et al. (2011) Chemical modulation of memory formation in larval zebrafish. Proc Natl Acad Sci U S A 108:15468-73
Jain, Roshan A; Wolman, Marc A; Schmidt, Lauren A et al. (2011) Molecular-genetic mapping of zebrafish mutants with variable phenotypic penetrance. PLoS One 6:e26510