Survival of spinal motor neurons during embryonic development requires the presence of its target tissue, skeletal muscle. Recent evidence suggests that a muscle-derived trophic factor is a component of this requirement for motor neuron survival, but the molecular nature of the factor is unknown. Our laboratory has partially purified a biologically-active protein from muscle tissues which stimulates neurite outgrowth from embryonic neurons in culture. This protein, which is unrelated to laminin, we refer to as muscle-derived neurotrophic factor (MDNTF)- The trophic protein promotes survival and development of chick embryonic motor neurons in vitro. Preliminary studies are presented which indicate that MDNTF also acts in vivo by enhancing the sprouting of motor axon terminals in the partially-denervated muscle of the adult rat. We hypothesize that MDNTF plays a role in the development and maintenance of motor neurons in vivo, influencing the initial growth, survival, or sprouting of motor axons. The overall objective of the proposed project is to identify a trophic factor present in striated muscle and investigate its roles in the in vivo survival and growth of motor neurons.
Aim A is designed to purify and characterize MDNTF. This will be accomplished by (i) establishment of quantitative bioassays for MDNTF, (ii) purification of MDNTF by chromatographic techniques and (iii) characterization of amino acid sequence and composition.
Aim B is designed to produce specific antibodies to MDNTF, assess its tissue localization, and clone complementary DNA (cDNA) for MDNTF. This will be accomplished by (i) production of polyclonal and monoclonal antibodies to MDNTF, (ii) immunocytochemical examination of MDNTF in tissues and (iii) cloning of cDNA for MDNTF.
Aim C is designed to investigate the role of MDNTF in motor neuron survival and growth in vivo. This will be accomplished by (i) assessment of motor neuron survival by injecting MDNTF or anti-MDNTF antibodies into chick embryos and (ii) assessment of sprouting by adult motor axon terminals after injecting MDNTF or anti-MDNTF antibodies into partially-denervated rat muscles. Successful outcome of this project is expected to provide definitive evidence for the existence and role of a muscle-derived trophic factor for motor neuron survival and growth in vivo. The results of these studies may contribute to an understanding of factors underlying progressive degenerative diseases of motor neurons such as amyotrophic lateral sclerosis.
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