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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Regulatory region in choline acetyltransferase gene directs developmental and tissue-specific expression in transgenic mice.
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Regulatory region in choline acetyltransferase gene directs developmental and tissue-specific expression in transgenic mice.

机译：胆碱乙酰基转移酶基因中的调节区指导转基因小鼠的发育和组织特异性表达。

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摘要

Acetylcholine, one of the main neurotransmitters in the nervous system, is synthesized by the enzyme choline acetyltransferase (ChAT; acetyl-CoA:choline O-acetyltransferase, EC 2.3.1.6). The molecular mechanisms controlling the establishment, maintenance, and plasticity of the cholinergic phenotype in vivo are largely unknown. A previous report showed that a 3800-bp, but not a 1450-bp, 5' flanking segment from the rat ChAT gene promoter directed cell type-specific expression of a reporter gene in cholinergic cells in vitro. Now we have characterized a distal regulatory region of the ChAT gene that confers cholinergic specificity on a heterologous downstream promoter in a cholinergic cell line and in transgenic mice. A 2342-bp segment from the 5' flanking region of the ChAT gene behaved as an enhancer in cholinergic cells but as a repressor in noncholinergic cells in an orientation-independent manner. Combined with a heterologous basal promoter, this fragment targeted transgene expression to several cholinergic regions of the central nervous system of transgenic mice, including basal forebrain, cortex, pons, and spinal cord. In eight independent transgenic lines, the pattern of transgene expression paralleled qualitatively and quantitatively that displayed by endogenous ChAT mRNA in various regions of the rat central nervous system. In the lumbar enlargement of the spinal cord, 85-90% of the transgene expression was targeted to the ventral part of the cord, where cholinergic alpha-motor neurons are located. Transgene expression in the spinal cord was developmentally regulated and responded to nerve injury in a similar way as the endogenous ChAT gene, indicating that the 2342-bp regulatory sequence contains elements controlling the plasticity of the cholinergic phenotype in developing and injured neurons.
机译：乙酰胆碱是神经系统中的主要神经递质之一，它是通过胆碱乙酰转移酶（ChAT；乙酰辅酶A：胆碱O-乙酰转移酶，EC 2.3.1.6）合成的。在体内，控制胆碱能表型的建立，维持和可塑性的分子机制尚不清楚。先前的报道显示，来自大鼠ChAT基因启动子的3800 bp，但不是1450 bp的5'侧翼片段，在体外指导胆碱能细胞中报告基因的细胞类型特异性表达。现在，我们已经鉴定了ChAT基因的远端调控区域，该区域可在胆碱能细胞系和转基因小鼠的异源下游启动子上赋予胆碱能特异性。 ChAT基因5'侧翼区的2342 bp片段以胆碱能独立的方式在胆碱能细胞中起增强子的作用，而在非胆碱能细胞中起阻抑剂的作用。与异源基底启动子结合，该片段将转基因表达靶向转基因小鼠中枢神经系统的几个胆碱能区域，包括基底前脑，皮质，脑桥和脊髓。在八个独立的转基因系中，转基因表达的模式定性和定量地平行于大鼠中枢神经系统各个区域的内源性ChAT mRNA所显示的模式。在脊髓的腰部增大中，转基因表达的85-90％靶向了胆碱能α运动神经元所在的腹侧。脊髓中的转基因表达受到发育调控，并以与内源性ChAT基因类似的方式对神经损伤作出反应，表明2342 bp的调控序列包含控制发育中和受损神经元中胆碱能表型可塑性的元素。

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