Nair Rajeevkumar Raveendran, Blankvoort Stefan, Lagartos Maria Jose, Kentros Cliff
Kavli Institute for Systems Neuroscience and Centre for Neural Computation, NTNU, Norway.
Kavli Institute for Systems Neuroscience and Centre for Neural Computation, NTNU, Norway; Institute of Neuroscience, University of Oregon, Eugene OR, USA.
iScience. 2020 Mar 27;23(3):100888. doi: 10.1016/j.isci.2020.100888. Epub 2020 Feb 7.
Although a variety of remarkable molecular tools for studying neural circuits have recently been developed, the ability to deploy them in particular neuronal subtypes is limited by the fact that native promoters are almost never specific enough. We recently showed that one can generate transgenic mice with anatomical specificity surpassing that of native promoters by combining enhancers uniquely active in particular brain regions with a heterologous minimal promoter, an approach we call EDGE (Enhancer-Driven Gene Expression). Here we extend this strategy to the generation of viral (rAAV) vectors, showing that some EDGE rAAVs can recapitulate the specificity of the corresponding transgenic lines in wild-type animals, even of another species. This approach thus holds the promise of enabling circuit-specific manipulations in wild-type animals, not only enhancing our understanding of brain function, but perhaps one day even providing novel therapeutic avenues to approach disorders of the brain.
尽管最近已经开发出了各种用于研究神经回路的卓越分子工具，但由于天然启动子几乎从来都不够特异，将它们应用于特定神经元亚型的能力受到了限制。我们最近表明，通过将在特定脑区中独特活跃的增强子与异源最小启动子相结合，能够生成解剖学特异性超过天然启动子的转基因小鼠，我们将这种方法称为EDGE（增强子驱动基因表达）。在这里，我们将这一策略扩展到病毒（rAAV）载体的生成，表明一些EDGE rAAV能够在野生型动物（甚至是另一个物种的动物）中重现相应转基因系的特异性。因此，这种方法有望在野生型动物中实现特定回路的操纵，不仅能增进我们对脑功能的理解，而且也许有朝一日甚至能提供治疗脑部疾病的新途径。
