MOLECULAR MECHANISMS REGULATING THE CHOLINERGIC SWITCH

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The adrenergic-cholinergic phenotype switch that occurs in vivo in a subset of developing sympathetic neurons is one of the best characterized models in developmental neurobiology. This model of neurotransmitter phenotype plasticity has provided a great deal of information about the role of cell- cell interactions in neuronal differentiation. It is particularly amenable to molecular analysis because the switch can be reproduced in culture by treating sympathetic neurons with well defined differentiation factors such as ciliary neurotrophic factor and leukemia inhibitory factor. A great deal is now known about the intercellular mediators of cholinergic differentiation; however the intracellular mechanisms of the cholinergic phenotype choice remain largely unexplored. Analysis of the molecular mechanisms underlying this phenotype switch in sympathetic neurons is likely to be particularly informative because the switch appears to involve a program of activation and repression of multiple genes including genes encoding neurotransmitter synthetic enzymes, neuropeptides, and neurotransmitter metabolizing enzymes. We hypothesize that one or a small number of transcription factors function as master controls for this program of cholinergic differentiation. We proposed to identify and characterize such transcription factors. We have cloned and expressed the rat choline acetyltransferase gene and have begun to map regulatory elements within the ChAT gene and coregulated neuropeptide genes which confer response to cholinergic differentiation factors. Nuclear proteins which bind to such elements are candidates for a role in the phenotype switch process. Nuclear proteins which may be involved in the switch will be cloned and their biological importance within the nervous system explored.