Remodeling of mature neural pathways involves both axonal outgrowth to establish new connections and axonal degeneration whereby terminations are eliminated. Mechanisms by which axon terminations are eliminated, or pruned, in the absence of cell death are poorly understood. Peripheral sympathetic innervation presents an especially tractable model for studying axon pruning under normal physiological and pathophysiological conditions. Sympathetic axon density in the virgin rodent uterus fluctuates rapidly during the estrous cycle, with terminal axons degenerating when estrogen levels rise and regenerating when they decline. We have shown that estrogen elevates uterine brain derived neurotrophic factor, and hypothesize that this contributes to sympathetic axon degeneration. We hypothesize that brain derived neurotrophic factor activates the p75 neurotrophin receptor, which stimulates intra-axonal ceramide formation. This promotes terminal axon degeneration through abnormal increases in membrane permeability and actin depolymerization. The present study investigates mechanisms whereby targets elicit selective terminal axon pruning.
The first aim evaluates the hypothesis that p75NTR activation is responsible for inducing sympathetic axon degeneration under physiological conditions.
In aim 2, we explore the hypothesis that p75NTR activation produces axon degeneration by increasing permeability of axonal membranes, and by promoting destabilization of the actin cytoskeleton.
In aim 3, we investigate the nature of ligands produced by the target that incur axon degeneration. Specifically, the roles of BDNF, pro-NGF and neurotrimin will be assessed. These studies use tractable in vivo and in vitro approaches to explore relationships among target- derived ligands, neural receptors, and signal transduction pathways, and will provide novel information on how selective terminal axon degeneration is accomplished under physiological and pathophysiological conditions. Findings will be pertinent to understanding both organizing principles related to normal nervous system plasticity, and to disturbances in innervation in certain disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS053796-04
Application #
7760986
Study Section
Special Emphasis Panel (ZRG1-NOMD-A (01))
Program Officer
Mamounas, Laura
Project Start
2007-02-01
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
4
Fiscal Year
2010
Total Cost
$318,274
Indirect Cost
Name
University of Kansas
Department
Physiology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Doss, Argenia L N; Smith, Peter G (2014) Langerhans cells regulate cutaneous innervation density and mechanical sensitivity in mouse footpad. Neurosci Lett 578:55-60
Doss, A L N; Smith, P G (2012) Nerve-Langerhans cell interactions in diabetes and aging. Histol Histopathol 27:1589-98
Krizsan-Agbas, Dora; Pedchenko, Tetyana; Smith, Peter G (2008) Neurotrimin is an estrogen-regulated determinant of peripheral sympathetic innervation. J Neurosci Res 86:3086-95