General guidance cues define the common pathways that axons follow and are responsible for the stereotyped anatomical patterns of axon outgrowth. Embryonic surgeries have established experimentally that three pairs of tissues provide general guidance cues for sensory and motor neurons in the chick embryo. All three pairs of tissues guide axons by providing a contrast between a """"""""path"""""""" that is permissive for axon advance and a """"""""barrier"""""""" that is relatively inhibitory and elicits active avoidance responses in the embryo. The central aims are to identify the cellular interactions that mediate the positive and avoidance responses of motor and sensory neurons to each of these paths and barriers and to begin to determine whether the mechanisms of general guidance are common to other neural populations and to neural crest cells. The first two aims will define the cellular interactions that mediate the responses of motor neurons (aim 1) and sensory neurons (aim 2) to each pair of paths/barriers. The contributions of chemotactic interactions and two different classes of contact-mediated interactions will be established using sensitive assays in culture. An analysis of how filopodial activities are altered by contact with path and barrier cells will provide the first detailed study of growth cone interactions with cells that have defined guidance roles in a vertebrate embryo. This work will identify the cellular mechanisms responsible for each of the pathfinding choices of sensory and motor growth cones.
Aim 3 will establish whether other PNS and CNS neurons can respond to a representative pair of paths/barriers in a sensitive culture assay and will thereby begin to define the extent to which these mechanisms are common.
Aim 4 asks if dermis is a transient barrier for both neural crest cells and sensory axons. Immunocytochemistry will show whether dermis transiently expresses markers typical of the known barriers, and embryonic surgeries will establish experimentally whether there is a temporal change in dermis from inhibitory to positive qualities.
Aim 5 addresses another temporal aspect of guidance. Embryonic surgeries will test the hypothesis that the dermamyotome is essential for neural crest cells to migrate to their ventral destination in the sympathetic ganglion before barriers to ventral migration develop. Individual studies in these aims will extend our understanding of mechanisms that guide motor neurons, sensory neurons and neural crest cells. The proposal as a whole will elucidate population-specific differences in general guidance, and will evaluate the possibility that the mechanisms of general guidance are common to many neurons and to neural crest cells. Identification of elements that guide axons and cells in the developing embryo is relevant to the treatment of lesions in human neural diseases and following injury.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurology A Study Section (NEUA)
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University of Michigan Ann Arbor
Schools of Arts and Sciences
Ann Arbor
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Steketee, Michael B; Tosney, Kathryn W (2002) Three functionally distinct adhesions in filopodia: shaft adhesions control lamellar extension. J Neurosci 22:8071-83
Steketee, M; Balazovich, K; Tosney, K W (2001) Filopodial initiation and a novel filament-organizing center, the focal ring. Mol Biol Cell 12:2378-95
Polinsky, M; Balazovich, K; Tosney, K W (2000) Identification of an invariant response: stable contact with schwann cells induces veil extension in sensory growth cones. J Neurosci 20:1044-55
Steketee, M B; Tosney, K W (1999) Contact with isolated sclerotome cells steers sensory growth cones by altering distinct elements of extension. J Neurosci 19:3495-506
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Tosney, K W; Dehnbostel, D B; Erickson, C A (1994) Neural crest cells prefer the myotome's basal lamina over the sclerotome as a substratum. Dev Biol 163:389-406
Oakley, R A; Tosney, K W (1993) Contact-mediated mechanisms of motor axon segmentation. J Neurosci 13:3773-92
Erickson, C A; Duong, T D; Tosney, K W (1992) Descriptive and experimental analysis of the dispersion of neural crest cells along the dorsolateral path and their entry into ectoderm in the chick embryo. Dev Biol 151:251-72
Oakley, R A; Tosney, K W (1991) Peanut agglutinin and chondroitin-6-sulfate are molecular markers for tissues that act as barriers to axon advance in the avian embryo. Dev Biol 147:187-206
Tosney, K W (1991) Cells and cell-interactions that guide motor axons in the developing chick embryo. Bioessays 13:17-23

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