1. Department of Molecular Genetics, College of Biological Sciences,
2. Human Cancer Genetics Program, Comprehensive Cancer Center,
3. Department of Molecular Virology Immunology and Medical Genetics, College of Medicine,
4. Department of Veterinary Biosciences, College of Veterinary Medicine, and,
5. Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA
6. These authors contributed equally to this work.
7. Present address: Department of Cell Biology and Molecular Medicine and University Hospital Cancer Center, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103, USA.

Correspondence to: Gustavo Leone^1,2,3 Correspondence and requests for materials should be addressed to G.L. (Email: Gustavo.Leone@osumc.edu).

Abstract

The E2F family is conserved from Caenorhabditis elegans to mammals, with some family members having transcription activation functions and others having repressor functions^{1, 2}. Whereas C. elegans³ and Drosophila melanogaster^{4, 5} have a single E2F activator protein and repressor protein, mammals have at least three activator and five repressor proteins^{1, 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 (E2f3a^3bki or E2f3a^1ki, 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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