Enhancer-Driven Gene Expression (EDGE) enables the generation of cell type specific tools for the analysis of neural circuits

Abstract

As in all circuits, fully understanding how neural circuits operate requires the ability to specifically manipulate individual circuit elements, i.e. particular neuronal cell types. While recent years saw the development of molecular genetic tools allowing one to control and monitor neuronal activity, progress is limited by the ability to express such transgenes specifically enough. This goal is complicated by the fact that we are only beginning to understand how many cell types exist in the mammalian brain. Obtaining neuronal cell type-specific expression requires co-opting the genetic machinery which specifies their striking diversity, typically done by making transgenic animals using promoters expressing in neurons. However, while the vast majority of genes express in the brain, they almost always express in multiple cell types, meaning native promoters are not specific enough. We have recently taken a new approach to increase the specificity of transgene expression based upon identifying the distal cis-regulatory genomic elements (i.e. enhancers) uniquely active in a brain region and combining them with a heterologous minimal promoter. Termed Enhancer-Driven Gene Expression (EDGE), it allows for the generation of transgenic animals targeting the cell types of any brain region with far greater specificity than can be obtained with native promoters. Moreover, their small size allows for the generation of cell-specific viral vectors, conceivably enabling circuit-specific manipulations to any species.

Keywords: Enhancers; Entorhinal cortex; Epigenetics; Neural circuits; Transcriptional control; Transgene expression; Transgenic methods; Transgenics.