MOLECULAR MECHANISMS REGULATING THE CHOLINERGIC SWITCH

在体内亚群中发生的肾上腺素能-胆碱能表型转换 交感神经元的发育是最具特征性的模型之一 在发育神经生物学方面。这种神经递质表型模型 可塑性提供了大量关于细胞角色的信息- 神经元分化中的细胞相互作用。它是特别顺从的 分子分析，因为开关可以在培养中通过 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。一位伟大的 Deal现在已经知道了胆碱能细胞间介质 分化；然而胆碱能的细胞内机制 表型选择在很大程度上仍未被探索。对分子的分析 交感神经元的这种表型转换背后的机制是 可能特别具有信息性，因为这种转变似乎涉及到 包括基因在内的多个基因的激活和抑制程序 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 许多转录因子对此起着主控作用。 胆碱能分化程序。我们建议确定和 描述这些转录因子的特征。我们已经克隆并表达了 大鼠胆碱乙酰转移酶基因及其调控图谱的构建 ChAT基因和共同调节的神经肽基因中的元件 对胆碱能分化因子的反应。核蛋白 与这些元素结合的是表型中的候选角色 切换进程。可能参与这种转换的核蛋白将 以及它们在神经系统中的生物学意义 探索过了。

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.