The E2F family is conserved from Caenorhabditis elegans to mammals, with some family members having transcription activation functions and others having repressor functions1,2. Whereas C. elegans3 and Drosophila melanogaster4,5 have a single E2F activator protein and repressor protein, mammals have at least three activator and five repressor proteins1,2,6. Why such genetic complexity evolved in mammals is not known. To begin to evaluate this genetic complexity, we targeted the inactivation of the entire subset of activators, E2f1, E2f2, E2f3a and E2f3b, singly or in combination in mice. We demonstrate that E2f3a is sufficient to support mouse embryonic and postnatal development. Remarkably, expression of E2f3b or E2f1 from the E2f3a locus (E2f3a3bki or E2f3a1ki , respectively) suppressed all the postnatal phenotypes associated with the inactivation of E2f3a. We conclude that there is significant functional redundancy among activators and that the specific requirement for E2f3a during postnatal development is dictated by regulatory sequences governing its selective spatiotemporal expression and not by its intrinsic protein functions. These findings provide a molecular basis for the observed specificity among E2F activators during development.
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We thank J. Moffitt and L. Rawahneh for histology expertise. We also thank J. Nevins, C. Bock and A. Otoshi for support in the generation of the E2f3a, E2f3b, E2f3a3bki and E2f3a1ki mice, and the Mouse Metabolic Phenotyping center at the University of Cincinnati for advice on the analysis of E2f1-/-E2f3a-/- mice. We are grateful to D. Guttridge, M. Ostrowski and M. Simcox for critically reading the manuscript and helpful suggestions. This work was funded by NIH grants to G.L. (R01CA85619, R01HD042619, R01CA121275, R01HD047470, P01CA097189), to L.W. (K01CA102328), DoD awards to A.d.B. (BC0300893) and J.-L.C. (BC061730), and a T32 fellowship (CA106196) to R.O. G.L. is the recipient of the Pew Charitable Trusts Scholar Award and the Leukemia and Lymphoma Society Scholar Award.
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Tsai, SY., Opavsky, R., Sharma, N. et al. Mouse development with a single E2F activator. Nature 454, 1137–1141 (2008). https://doi.org/10.1038/nature07066
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