The wide array of neurological disease and psychiatric disorders associated with imbalances in the catecholamine (CA) neurotransmitter systems serves to underscore their critical importance in the proper functioning of the brain. The availability of CA neurotransmitters is largely determined by regulation of the rate- limiting enzyme, tyrosine hydroxylase (TH). Studies from this laboratory have demonstrated the existence, in muscle, of an agents(s) with the unique ability to induce novel expression of the TH gene. Because of its capacity to alter the differentiative fate of certain brain neurons in culture, this factor (or combination of factors) was broadly termed muscle-derived differentiation factor (MDF). Progress over the last three years has clearly indicated the the """"""""MDF response"""""""" requires participation of at least two substances present in muscle: acidic fibroblast growth facto (aFGF) and an unidentified molecule. The investigators have found that, like the muscle agent, neurotransmitters were also important aFGF partners. Specifically, catechol-containing transmitters, which had no ability to induce TH on their own, were able to do so if co-incubated with aFGF. Studies are therefore proposed to examine the molecular processes involved in TH induction by both aFGF and the catechol neurotransmitters and the role of each in the establishment of a CA phenotype during development and in the modulation of that expression in models of disease.
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