Transgenic analysis of central nervous system development and regeneration.

U Lendahl
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引用次数: 149

Abstract

The transgenic technique allows specific genetic alterations to be made in all cells of an animal and this has greatly improved our understanding of how the embryonic and adult central nervous system (CNS) develop. The CNS originates from the neuroectoderm in the neural plate on the dorsal side of the embryo and after closure of the neural tube the cells of the neuroepithelium, i.e. the CNS stem cells, transiently proliferate to generate neurons and glial cells. Here we review our attempts to gain insights into the control of CNS development. We have identified a gene, nestin, which is predominantly expressed in embryonic and adult CNS stem cells. In addition to its normal expression in the CNS stem cells, nestin is reexpressed in CNS tumors and in the adult spinal cord and brain after CNS injury. By using the lacZ reporter gene assay in transgenic mice, we have identified regulatory regions (enhancer) in the nestin gene required for expression in embryonic CNS stem cells and in the adult spinal cord after injury. In a second project, we have cloned and characterized the Notch gene family (the Notch 1, 2 and 3 genes) in mouse and man. These genes encode trans-membrane receptors, which appear to be key regulatory molecules for proliferation and differentiation both in the developing CNS and in other tissues. Expression of an activated form of the Notch 3 receptor from the nestin promoter in transgenic mice leads to a lethal, exencephaly-like phenotype in the embryo, probably as a result of excess proliferation of the CNS stem cells. The recent finding that the Notch 3 gene is the genetic cause for familial stroke is discussed in the context of current models for Notch function.

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中枢神经系统发育与再生的转基因分析。
转基因技术允许在动物的所有细胞中进行特定的遗传改变,这极大地提高了我们对胚胎和成年中枢神经系统(CNS)如何发育的理解。中枢神经系统起源于胚胎背侧神经板的神经外胚层,神经管闭合后,神经上皮细胞即中枢神经系统干细胞短暂增殖生成神经元和胶质细胞。在这里,我们回顾了我们试图深入了解中枢神经系统发育的控制。我们已经确定了一个基因,巢蛋白,主要在胚胎和成人中枢神经系统干细胞中表达。除了在中枢神经系统干细胞中正常表达外,nestin在中枢神经系统损伤后,在中枢神经系统肿瘤以及成人脊髓和脑中也重新表达。通过在转基因小鼠中使用lacZ报告基因试验,我们已经确定了巢蛋白基因在胚胎中枢神经系统干细胞和成年脊髓损伤后表达所需的调控区域(增强子)。在第二个项目中,我们克隆并鉴定了小鼠和人的Notch基因家族(Notch 1、2和3基因)。这些基因编码跨膜受体,它们似乎是发育中的中枢神经系统和其他组织中增殖和分化的关键调节分子。在转基因小鼠中,巢蛋白启动子中Notch 3受体的激活形式的表达会导致胚胎中出现致命的畸形样表型,这可能是由于中枢神经系统干细胞过度增殖的结果。最近发现Notch 3基因是家族性中风的遗传原因,在当前Notch功能模型的背景下进行了讨论。
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