This project seeks to determine the cellular and molecular basis for the accurate pathfinding ability of embryonic, vertebrate spinal cord motor and sensory neurons. The importance of known cell adhesion-recognition molecules (L1, NCAM, axonin-1/TAG-1, the polysialic moiety of NCAM) on axonal outgrowth will be assessed by perturbing the function of these molecules via in-ovo injection of antibodies or enzymes, and by following up these observations in culture. The signal transduction pathways used and cytoskeletal rearrangements made as growth cones orient to gradients of putative chemotactic substances will be studied in culture. Special effort will be devoted to understanding how the expression of the 5E10 antigen is regulated; the 5E10 monoclonal antibody recognizes a specific phosphorylated state of a cytoskeletal element (probably the middle weight neurofilament subunit) which occurs in growth cones as they detect and respond to specific target derived guidance cues. The importance of this phosphorylation event in pathfinding will be assessed by determining the consequence of misexpression of this antigen. The information to be obtained is relevant to improving neural regeneration and functional recovery following peripheral nerve or spinal cord injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS019640-18
Application #
2839290
Study Section
Neurology B Subcommittee 2 (NEUB)
Program Officer
Leblanc, Gabrielle G
Project Start
1983-01-01
Project End
2000-08-31
Budget Start
1998-12-01
Budget End
2000-08-31
Support Year
18
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Hata, Katsusuke; Maeno-Hikichi, Yuka; Yumoto, Norihiro et al. (2018) Distinct Roles of Different Presynaptic and Postsynaptic NCAM Isoforms in Early Motoneuron-Myotube Interactions Required for Functional Synapse Formation. J Neurosci 38:498-510
Kastanenka, Ksenia V; Landmesser, Lynn T (2013) Optogenetic-mediated increases in in vivo spontaneous activity disrupt pool-specific but not dorsal-ventral motoneuron pathfinding. Proc Natl Acad Sci U S A 110:17528-33
Maeno-Hikichi, Yuka; Polo-Parada, Luis; Kastanenka, Ksenia V et al. (2011) Frequency-dependent modes of synaptic vesicle endocytosis and exocytosis at adult mouse neuromuscular junctions. J Neurosci 31:1093-105
Park, Gyu-Hwan; Maeno-Hikichi, Yuka; Awano, Tomoyuki et al. (2010) Reduced survival of motor neuron (SMN) protein in motor neuronal progenitors functions cell autonomously to cause spinal muscular atrophy in model mice expressing the human centromeric (SMN2) gene. J Neurosci 30:12005-19
Kastanenka, Ksenia V; Landmesser, Lynn T (2010) In vivo activation of channelrhodopsin-2 reveals that normal patterns of spontaneous activity are required for motoneuron guidance and maintenance of guidance molecules. J Neurosci 30:10575-85
Wang, Sheng; Polo-Parada, Luis; Landmesser, Lynn T (2009) Characterization of rhythmic Ca2+ transients in early embryonic chick motoneurons: Ca2+ sources and effects of altered activation of transmitter receptors. J Neurosci 29:15232-44
Kariya, Shingo; Park, Gyu-Hwan; Maeno-Hikichi, Yuka et al. (2008) Reduced SMN protein impairs maturation of the neuromuscular junctions in mouse models of spinal muscular atrophy. Hum Mol Genet 17:2552-69
Hanson, M Gartz; Milner, Louise D; Landmesser, Lynn T (2008) Spontaneous rhythmic activity in early chick spinal cord influences distinct motor axon pathfinding decisions. Brain Res Rev 57:77-85
Hata, Katsusuke; Polo-Parada, Luis; Landmesser, Lynn T (2007) Selective targeting of different neural cell adhesion molecule isoforms during motoneuron myotube synapse formation in culture and the switch from an immature to mature form of synaptic vesicle cycling. J Neurosci 27:14481-93
Herlitze, Stefan; Landmesser, Lynn T (2007) New optical tools for controlling neuronal activity. Curr Opin Neurobiol 17:87-94

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