Combinatorial genetic strategies for dissecting cell lineages, cell types, and gene function in the mouse brain

Research in neuroscience has greatly benefited from the development of genetic approaches that enable lineage tracing, cell type targeting, and conditional gene regulation. Recent advances in combinatorial strategies, which integrate multiple cellular features, have significantly enhanced the spatiotemporal precision and flexibility of these manipulations. In this minireview, we introduce the concept and design of these strategies and provide a few examples of their application in genetic fate mapping, cell type targeting, and reversible conditional gene regulation. These advancements have facilitated in-depth investigation into the developmental principles underlying the assembly of brain circuits, granting experimental access to highly specific cell lineages and subtypes, as well as offering valuable new tools for modeling and studying neurological diseases. Additionally, we discuss future directions aimed at expanding and improving the existing genetic toolkit for a better understanding of the development, structure, and function of healthy and diseased brains. This minireview introduces the concept of and advances in combinatorial genetic strategies integrating multiple cellular features for improved spatiotemporal precision and flexibility in lineage tracing, cell type targeting, and conditional gene regulation in the brain. It also discusses future directions for expanding and improving this genetic toolkit.image