Hommel Jonathan D, Sears Robert M, Georgescu Dan, Simmons Diana L, DiLeone Ralph J
Department of Psychiatry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, Texas 75390-9070, USA.
Nat Med. 2003 Dec;9(12):1539-44. doi: 10.1038/nm964. Epub 2003 Nov 23.
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.
能够对基因表达进行空间和时间控制的条件性突变技术可用于创建具有受限基因修饰的小鼠。这些小鼠是强大的疾病模型，其中成年组织中的基因功能可被特异性剖析。然而，当前的条件性基因操作策略效率低下，且往往缺乏足够的空间控制。在此，我们利用病毒介导的RNA干扰（RNAi）在成年小鼠的中脑神经元内特异性敲低编码多巴胺合成酶酪氨酸羟化酶的基因Th。这种局部基因敲低导致行为改变，包括运动性能缺陷和对精神兴奋剂反应降低。这些结果强调了利用病毒介导的RNAi快速建立和测试新型遗传疾病模型的潜力。类似策略可能用于其他模式物种，并最终可能在人类基因治疗中找到应用。
