The mechanisms by which neuromuscular junctions are established either during the course of embryonic development or following denervation are little understood. The specific objective of this proposal is to test the hypothesis that an interaction of the developing motor nerve fibers with muscle cells triggers the development of postsynaptic specializations on the embryonic muscle cells. I will monitor the development of aneural superior oblique muscle of the eye to determine if the postsynaptic specializations develop in the absence of motor nerve fibers. Muscle will be made aneural by permanent destruction of the trochlear motor neurons well in advance of their normal projection to the muscle. I will monitor the development of synaptic folds, postsynaptic densities, acetylcholinesterase and basal lamina in normal and aneural muscles at the light and electron microscopic levels. In addition, I propose to determine if the number of neuromuscular junctions is regulated by the number of motor neurons innervating the muscle. Immunoglobulin G from patients with myasthenia gravis is known to prevent the death of trochlear motor neurons which occurs normally during the course of embryonic development. Myasthenia gravis immunoglobulin G will be used to hyperinnervate the muscle. I will monitor the total number of neuromuscular junctions in normal and hyperinnervated muscles at the light microscopic level. This proposal fits in with my long-term research objective which is to understand the nature of mechanisms and signals between the nerve and muscle, both during the course of normal development, and in diseases affecting motor neurons, neuromuscular junctions and muscle. The investigation proposed here will rigorously test whether the motor nerve is necessary for the differentiation of the postsynaptic elements of the neuromuscular junction or whether the differentiation of the postsynaptic specializations is preprogrammed in the developing muscle cell. Further, it will reveal whether the total number of neuromuscular synapses in the muscle is controlled by the nerve or whether it is preprogrammed in the muscle. The results of this investigation will also increase our basic understanding of the mechanisms by which synapses are formed during embryogenesis.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD018280-03
Application #
3315298
Study Section
Human Embryology and Development Subcommittee 2 (HED)
Project Start
1983-12-01
Project End
1987-11-30
Budget Start
1985-12-01
Budget End
1987-11-30
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Medical College of Georgia (MCG)
Department
Type
Schools of Medicine
DUNS #
City
Augusta
State
GA
Country
United States
Zip Code
30912
Sohal, G S (1995) Sixth Annual Stuart Reiner Memorial Lecture: embryonic development of nerve and muscle. Muscle Nerve 18:2-14
Hirano, S; Fuse, S; Sohal, G S (1991) The effect of the floor plate on pattern and polarity in the developing central nervous system. Science 251:310-3
Sohal, G S (1988) Development of postsynaptic-like specializations of the neuromuscular synapse in the absence of motor nerve. Int J Dev Neurosci 6:553-65
Yamashita, T; Sohal, G S (1987) Embryonic origin of skeletal muscle cells in the iris of the duck and quail. Cell Tissue Res 249:31-7
Sohal, G S; Sickles, D W (1986) Embryonic differentiation of fibre types in normal, paralysed and aneural avian superior oblique muscle. J Embryol Exp Morphol 96:79-97
Sohal, G S; Arumugam, T; Swift, T R (1986) Increased motor neuron projection during development does not increase the number of neuromuscular synapses. Exp Neurol 92:284-8
Sohal, G S; Stoney Jr, S D; Arumugam, T et al. (1986) Influence of reduced neuron pool on the magnitude of naturally occurring motor neuron death. J Comp Neurol 247:516-28
Yamashita, T; Sohal, G S (1986) Development of smooth and skeletal muscle cells in the iris of the domestic duck, chick and quail. Cell Tissue Res 244:121-31
Sohal, G S; Knox, T S; Allen Jr, J C et al. (1985) Development of the trochlear nucleus in quail and comparative study of the trochlear nucleus, nerve, and innervation of the superior oblique muscle in quail, chick, and duck. J Comp Neurol 239:227-36
Arumugam, T; Sohal, G S (1985) Myotube clusters do not bear any quantitative relation to the extent of motoneuron survival. Exp Neurol 90:281-6