Local gene knockdown in the brain using viral-mediated RNA interference
Local gene knockdown in the brain using viral-mediated RNA interference
复制标题
DOI：
10.1038/nm964
复制
发表时间：
2003-12-01
期刊：
影响因子：
82.9
通讯作者：
DiLeone, RJ
中科院分区：
文献类型：
--
作者：
Hommel, JD;Sears, RM;DiLeone, RJ
允许对基因表达进行空间和时间控制的条件突变技术可用于产生具有限制性遗传修饰的小鼠。这些小鼠作为强大的疾病模型，其中成年组织中的基因功能可以被特异性地解剖。然而，目前的有条件遗传操作策略效率低下，而且往往缺乏足够的空间控制。在这里，我们使用病毒介导的RNA干扰（RNAi）产生一个特定的敲低Th，多巴胺合成酶酪氨酸羟化酶的基因编码，在成年小鼠中脑神经元。这种局部基因敲除导致行为改变，包括运动表现缺陷和对精神兴奋剂的反应降低。这些结果强调了使用病毒介导的RNAi用于快速生产和测试新的遗传疾病模型的潜力。类似的策略可以用于其他模式物种，并可能最终在人类基因治疗中找到应用。
Conditional mutant techniques that allow spatial and temporal control over gene expression can be used to create mice with restricted genetic modifications. These mice serve as powerful disease models in which gene function in adult tissues can be specifically dissected. Current strategies for conditional genetic manipulation are inefficient, however, and often lack sufficient spatial control. Here we use viral- mediated RNA interference (RNAi) to generate a specific knockdown of Th, the gene encoding the dopamine synthesis enzyme tyrosine hydroxylase, within midbrain neurons of adult mice. This localized gene knockdown resulted in behavioral changes, including a motor performance deficit and reduced response to a psychostimulant. These results underscore the potential of using viral- mediated RNAi for the rapid production and testing of new genetic disease models. Similar strategies may be used in other model species, and may ultimately find applications in human gene therapy.