Determination of the physiological and pathological roles of E2F3 in adult tissues
Nature Publishing Group
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Gamper, I., Burkhart, D., Bywater, M., Garcia, D., Wilson, C., Kreuzaler, P., Arends, M., et al. (2017). Determination of the physiological and pathological roles of E2F3 in adult tissues. Scientific Reports, 7 (9932)https://doi.org/10.1038/s41598-017-09494-6
While genetically engineered mice have made an enormous contribution towards the elucidation of human disease, it has hitherto not been possible to tune up or down the level of expression of any endogenous gene. Here we describe compound genetically modified mice in which expression of the endogenous E2f3 gene may be either reversibly elevated or repressed in adult animals by oral administration of tetracycline. This technology is, in principle, applicable to any endogenous gene, allowing direct determination of both elevated and reduced gene expression in physiological and pathological processes. Applying this switchable technology to the key cell cycle transcription factor E2F3, we demonstrate that elevated levels of E2F3 drive ectopic proliferation in multiple tissues. By contrast, E2F3 repression has minimal impact on tissue proliferation or homeostasis in the majority of contexts due to redundancy of adult function with E2F1 and E2F2. In the absence of E2F1 and E2F2, however, repression of E2F3 elicits profound reduction of proliferation in the hematopoietic compartments that is rapidly lethal in adult animals.
This work was supported by CRUK (Programme Grant A12077), the ERC (Advanced Investigator Award 294851), and the NCI (grants CA98018, CA100193) (all to G.I.E.). D.G. was supported by NIGMS grant #1 R25 GM56847. MB was funded by an EMBO Long-term fellowship and an Australian NHMRC Early Career Fellowship.
Cancer Research UK (12077)
European Research Council (294851)
Cancer Research UK (19013)
European Molecular Biology Organization (EMBO) (EMBO ALTF 330-2013)
External DOI: https://doi.org/10.1038/s41598-017-09494-6
This record's URL: https://www.repository.cam.ac.uk/handle/1810/267477
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