MOLECULAR MECHANISMS REGULATING THE CHOLINERGIC SWITCH

肾上腺素能-胆碱能表型转换发生在体内的一个子集 交感神经元的发育是最好的模型之一， 发育神经生物学的研究 这种神经递质表型模型 可塑性提供了大量关于细胞作用的信息， 神经元分化中的细胞相互作用。 它特别适合 分子分析，因为开关可以在培养中复制， 用明确的分化因子治疗交感神经元， 作为睫状神经营养因子和白血病抑制因子。 一个伟大 现在人们对胆碱能细胞间介质的了解已经很多 分化;然而，胆碱能细胞的细胞内机制 表型的选择在很大程度上还未被探索。 分子分析 交感神经元中这种表型转换的潜在机制是 可能特别有用，因为开关似乎涉及 一个激活和抑制多个基因的程序，包括基因 编码神经递质合成酶，神经肽，和 神经递质代谢酶。 我们假设一个或一个小的 许多转录因子作为这一过程的主控制 胆碱能分化程序。 我们建议确定和 描述这些转录因子。 我们克隆并表达了 大鼠胆碱乙酰转移酶基因，并已开始映射调控 ChAT基因内的元件和共调节的神经肽基因， 赋予对胆碱能分化因子的反应。 核蛋白 结合到这些元件上的是在表型中起作用的候选者 切换过程 可能参与转换的核蛋白质将 以及它们在神经系统中的生物学重要性 探讨了

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.