期刊
NATURE METHODS
卷 19, 期 2, 页码 205-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41592-021-01364-4
关键词
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资金
- National Institutes of Health [R01OD020376, P30EY001765, R01NS095355, R01HG009518]
- Royal Society of New Zealand Marsden grant [VUW1902]
- HRC Explorer grant (Health Research Council of New Zealand) [19/750]
- Research to Prevent Blindness
Researchers have developed an improved NTR 2.0 variant through rational engineering and cross-species screening, which significantly enhances cell-specific ablation efficacy without the need for toxic prodrug treatment. This discovery allows for enhanced investigations into cell function, stem cell niche regenerative capacity, and chronic degenerative diseases.
Transgenic expression of bacterial nitroreductase (NTR) enzymes sensitizes eukaryotic cells to prodrugs such as metronidazole (MTZ), enabling selective cell-ablation paradigms that have expanded studies of cell function and regeneration in vertebrates. However, first-generation NTRs required confoundingly toxic prodrug treatments to achieve effective cell ablation, and some cell types have proven resistant. Here we used rational engineering and cross-species screening to develop an NTR variant, NTR 2.0, which exhibits similar to 100-fold improvement in MTZ-mediated cell-specific ablation efficacy, eliminating the need for near-toxic prodrug treatment regimens. NTR 2.0 therefore enables sustained cell-loss paradigms and ablation of previously resistant cell types. These properties permit enhanced interrogations of cell function, extended challenges to the regenerative capacities of discrete stem cell niches, and novel modeling of chronic degenerative diseases. Accordingly, we have created a series of bipartite transgenic reporter/effector resources to facilitate dissemination of NTR 2.0 to the research community.
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