The long term goal of the proposed research is to examine the role of a variety of purified neurotrophic agents in promoting the survival and differentiation of mammalian neurons in vivo, including motoneurons (MNs), dorsal root ganglia (DRG), sympathetic ganglia, and spinal interneurons during normal development and following injury. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), ciliary neurotrophic factor (CNTF), and the muscle-derived protein, choline acetyltransferase development factor (CDF), will be used to treat mouse embryos in utero during periods of naturally occurring neuronal death. At the end of the cell death period, treated and control embryos will be evaluated regarding the development of a number of different properties of peripheral and central neurons. These include measures of neuron survival and differentiation and measures of target development and innervation. In addition, we will determine whether the injury-induced death of motor and sensory neurons that occurs following axotomy of peripheral nerves in fetal and neonatal mice can be prevented by treatment with these trophic agents. We will also examine whether postnatal administration of these proteins alters the development of normal neuron properties such as soma size, dendritic arbors, and biochemical differentiation. Previous studies have shown that some of the trophic agents to be employed here promote sensory, sympathetic, and motor neuron survival in vivo in the chick embryo. The planned studies are novel in that they represent the first attempt to demonstrate an in vivo effect of neurotrophic agents, including muscle- derived agents, on mammalian MN development and survival. These studies are an important step in determining whether trophic agents are involved in the death of MNs in motor neuron disease and may be especially significant for understanding the pathological mechanisms in Infantile Progressive Spinal Muscular Atrophy (Werdnig-Hoffman Disease) and Amyotrophic Lateral Sclerosis (ALS).
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