Experiments and observations are proposed whose long-term goal is to attain a better understanding of the mechanisms underlying naturally-occurring motoneuron death in the chick embryo. A major focus of these studies is to further explore the role of neuromuscular activity, targets and target-derived survival (neurotrophic) factors in the normal death of spinal motoneurons. Transplants of spinal cord between different segmental levels (e.g., thoracic to lumbar) will be used to determine: (1) the effect of foreign targets on motoneuron development and survival; and (2) the effect of foreign innervation on target (muscle) differentiation. Another set of studies will use an in vitro isolated spinal cord-limb preparation for assessing the roles of impulse activity, synaptic transmission and muscle contraction in regulating the rate and amount of motoneuron death. An avian mutant, crooked neck dwarf (cn/cn) which exhibits muscular dysgenesis and a lack of spontaneous movement at embryonic stages will be examined in an attempt to: (1) locate the major site(s) of gene action (neural, muscular, both); (2) better characterize the phenotypic expression of the mutation during development; and (3) relate the genetic defect to the lack of altered motoneuron survival. Finally, a set of studies are planned to characterize the effects of serum from patients with amyotrophic lateral sclerosis (ALS) and of embryonic muscle extracts on motoneuron survival in the chick embryo, in ovo. In addition to further defining the effects of these agents on motoneuron and muscle development, a collaborative effort is planned to begin to purify and characterize active factors from these sources (ALS, embryonic muscle extract) and test their effects in vivo. The proposed studies may lead to a better understanding of the neurobiological basis of pathological disorders that involve altered neuronal survival.
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