Mouse development with a single E2F activator

• Published in: Nature 2008-08, Vol.454 (7208), p.1137-1141
• Main Authors: Chong, Jean-Leon, Naidu, Shan, Timmers, Cynthia, Nolan, Eric, Leone, Gustavo, Feria-Arias, Enrique, Sharma, Nidhi, Opavska, Jana, Opavsky, Rene, Rosol, Thomas J, Wu, Lizhao, Tsai, Shih-Yin, de Bruin, Alain, Trikha, Prashant, Stromberg, Paul, Fernandez, Soledad A
• Format: Article
• Language: English
• Subjects: Adipose tissue; Animals; Biological and medical sciences; Caenorhabditis elegans; Cells, Cultured; DNA binding proteins; Drosophila; E2F Transcription Factors - deficiency; E2F Transcription Factors - genetics; E2F Transcription Factors - metabolism; E2F1 Transcription Factor - deficiency; E2F1 Transcription Factor - genetics; E2F1 Transcription Factor - metabolism; E2F2 Transcription Factor - deficiency; E2F2 Transcription Factor - genetics; E2F2 Transcription Factor - metabolism; E2F3 Transcription Factor - deficiency; E2F3 Transcription Factor - genetics; E2F3 Transcription Factor - metabolism; Embryo Loss - genetics; Embryo, Mammalian - embryology; Embryo, Mammalian - metabolism; Embryology: invertebrates and vertebrates. Teratology; Embryonic Development - genetics; Fundamental and applied biological sciences. Psychology; Gene Deletion; Genetic aspects; Genomics; Genotype; Growth; Growth - genetics; Humanities and Social Sciences; letter; Mammals; Mice; Mice, Knockout; Molecular embryology; multidisciplinary; Phenotype; Physiological aspects; Properties; Proteins; Rodents; Science; Science (multidisciplinary)
• ISSN: 0028-0836; 1476-4687; 1476-4679
• DOI: 10.1038/nature07066

The E2F family is conserved from Caenorhabditis elegans to mammals, with some family members having transcription activation functions and others having repressor functions. Whereas C. elegans and Drosophila melanogaster have a single E2F activator protein and repressor protein, mammals have at least three activator and five repressor proteins. 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.