MOLECULAR GENETICS OF BIOGENIC AMINE NEURONS

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The experiments proposed herein are designed to further our understanding of development and function of monoamine neurons and monoamines in the nervous system. Aberrant neurotransmitter levels and defects in monoamine neurons have been observed in association with a number of human pathologies (e.g. Parkinson's disease, phenylketoneurea, schizophrenia etc.). The long term objectives of the proposed research are to develop genetic variants and molecular probes that will allow manipulation of the biogenic amine synthesis in the model system, Drosophila melanogaster, for each amine (serotonin, dopamine and octopamine), and to perturb the transmitter phenotype of monoamine containing neurons by creation of novel genetic variants. Biological consequences of perturbations in amine level and amine specificity for each individual neuronal subsets will be analyzed in the conventional and novel genetic variants. Specifically molecular genetics of genes encoding tryptophan hydroxylase, tyrosine hydroxylase and tyramine beta hydroxylase will be developed, so that it will be possible to manipulate synthesis of each amine, and promoter sequences that can confer cell type specific expression are cloned and characterized. These goals will be approached using experimental strategies that depend on molecular and genetic methodologies, many of which are unique to Drosophila. These methodologies will be used in conjunction with the current anatomical, histochemical, biochemical and immunohistochemical approaches. Molecular probes and genetic variants developed here will augment and complement the current cellular and biochemical understanding of by far the best characterized set of neurons in the nervous system.