Neurotrophic factors are messengers in the communication between neurons. They regulate neuronal differentiation and function. Internalization, intracellular transport, signal transduction and eventual degradation are essential steps in trophic signaling. Recent studies have shown that internalized neurotrophins can be sorted into either degradative or recycling pathways. The application's central aim is to elucidate how internalized neurotrophins are sorted into distinct intracellular pathways. This research will be done primarily at the Nencki Institute in Poland as an extension of NIH grant # RO 1 EY 12841. The proposed studies will utilize the developing visual system of chick embryos as a unique invivo model system which allows the introduction of radiolabeled trophic factors into a compartment and the quantification of intracellular pathways. Experiments will focus on the comparison of different subcellular pathways after internalization of neurotrophins by dendrites (retinal ganglion cells) and after internalization exclusively by axon terminals (isthmo-optic neurons). These experiments will show how the route of uptake (dendritic vs. axonal) influences the subsequent signaling and degradation pathways. Autoradiography at the ultrastructural level will be used to identify the subcellular distribution of neurotrophins. Distribution profiles will be compared between neurotrophins. Receptor binding of invivo- transported neurotrophins will be determined by crosslinking and immunoprecipitation with receptor-specific antibodies. The organelles in which internalized neurotrophins accumulate and their pathways and subcellular destinations will be compared and experimentally manipulated by competition with heterologous neurotrophins and inactivation of tyrosine kinase receptors. The combination of molecular, pharmacological and ultrastructural approaches will allow us to answer questions about trafficking of neurotrophins which are crucial to an understanding of how these factors may regulate events as diverse as neuronal survival and synaptic plasticity. Neurodegenerative diseases have been related to deficits in trophic support. Knowledge about the normal trafficking, sorting and recycling of neurotrophic factors will help us to understand pathologic conditions and how exogenous neurotrophins may be used as therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Small Research Grants (R03)
Project #
5R03TW005700-03
Application #
6643558
Study Section
International and Cooperative Projects 1 Study Section (ICP)
Program Officer
Michels, Kathleen M
Project Start
2001-09-01
Project End
2004-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
3
Fiscal Year
2003
Total Cost
$40,320
Indirect Cost
Name
University of Nevada Reno
Department
Physiology
Type
Schools of Medicine
DUNS #
146515460
City
Reno
State
NV
Country
United States
Zip Code
89557
Von Bartheld, Christopher S; Altick, Amy L (2011) Multivesicular bodies in neurons: distribution, protein content, and trafficking functions. Prog Neurobiol 93:313-40
Butowt, Rafal; von Bartheld, Christopher S (2009) Fates of neurotrophins after retrograde axonal transport: phosphorylation of p75NTR is a sorting signal for delayed degradation. J Neurosci 29:10715-29
Rind, Howard B; Butowt, Rafal; von Bartheld, Christopher S (2005) Synaptic targeting of retrogradely transported trophic factors in motoneurons: comparison of glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, and cardiotrophin-1 with tetanus toxin. J Neurosci 25:539-49
Butowt, Rafal; von Bartheld, Christopher S (2005) Anterograde axonal transport of BDNF and NT-3 by retinal ganglion cells: roles of neurotrophin receptors. Mol Cell Neurosci 29:11-25
von Bartheld, Christopher S; Baker, Clare V H (2004) Nervus terminalis derived from the neural crest? A surprising new turn in a century-old debate. Anat Rec B New Anat 278:12-3
von Bartheld, Christopher S (2004) Axonal transport and neuronal transcytosis of trophic factors, tracers, and pathogens. J Neurobiol 58:295-314
Caleo, Matteo; Medini, Paolo; von Bartheld, Christopher S et al. (2003) Provision of brain-derived neurotrophic factor via anterograde transport from the eye preserves the physiological responses of axotomized geniculate neurons. J Neurosci 23:287-96
Chen, Jennifer; Butowt, Rafal; Rind, Howard B et al. (2003) GDNF increases the survival of developing oculomotor neurons through a target-derived mechanism. Mol Cell Neurosci 24:41-56
Wang, Xiaoxia; Butowt, Rafal; von Bartheld, Christopher S (2003) Presynaptic neurotrophin-3 increases the number of tectal synapses, vesicle density, and number of docked vesicles in chick embryos. J Comp Neurol 458:62-77
Butowt, Rafal; von Bartheld, Christopher S (2003) Connecting the dots: trafficking of neurotrophins, lectins and diverse pathogens by binding to the neurotrophin receptor p75NTR. Eur J Neurosci 17:673-80

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