In most higher animals, injury to axons within the central nervous system (CNS) leads to the death of axotomized neurons, probably due to loss of target-derived growth factors. The long-term goal of this research is to understand the mechanisms by which growth factors promote the survival of axotomized ganglion cells in the retina. Due to its great accessibility, and ability to regenerate, the frog visual system is an excellent model with which to address this question. After lesioning the frog optic nerve, regeneration occurs and retinal ganglion cells (RGCs) reconnect to their targets. Nevertheless, approximately 50% of the retinal ganglion cells die. We have shown that application of fibroblast growth factor-2 (FGF-2) prevents this cell death in the retina, but only when it is applied to the optic nerve stump. There is accumulating evidence from in vitro studies that the signaling pathways activated by neurotrophins differ based on the location of stimulation, but little is known about how this site-specificity affects the responses to neurotrophins in vivo. In this proposal, we will determine the different intracellular signaling pathways that are activated by the neurotrophic factor FGF-2 when it is applied to the cut nerve, compared to intraocular application, that may explain its location-specific effects on neuronal survival. In the first aim we will test the hypothesis that FGF-2 applied to the cut axons, but not to the cell bodies, activates the transcription factor CREB via the MAPK pathway, in particular via Erk1/2. In the second aim we will determine the mechanisms by which FGF-2 upregulates the synthesis of brain-derived neurotrophic factor (BDNF), another neurotrophin essential for retinal ganglion cell survival, and of the BDNF receptor, TrkB. Finally, in the third aim we will investigate the location-specific effects and signaling pathways of BDNF itself, and determine how the site of application of the factor affects retinal ganglion cell survival. The proposed research will make a significant contribution towards understanding how neurotrophins modulate neuronal survival in a location-specific manner, in an in vivo adult system, which should lead to improved therapeutic methods to promote recovery after injury and disease.
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