Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mouse development with a single E2F activator

Nature volume 454, pages 1137–1141 (2008)Cite this article

Abstract

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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Generation of E2f3a and E2f3b knockout mice.
Figure 2: Genotypic analysis of embryos and offspring deficient for various combinations of activating E2Fs.
Figure 3: E2f1 and E2f3a are essential for postnatal development.
Figure 4: Expression of E2f3b or E2f1 from the E2f3a locus suppresses phenotypes owing to loss of E2f3a.

References

  1. Trimarchi, J. M. & Lees, J. A. Sibling rivalry in the E2F family. Nature Rev. Mol. Cell Biol. 3, 11–20 (2002)

    Article  CAS  Google Scholar 

  2. Attwooll, C., Lazzerini Denchi, E. & Helin, K. The E2F family: specific functions and overlapping interests. EMBO J. 23, 4709–4716 (2004)

    Article  CAS  Google Scholar 

  3. Ceol, C. J. & Horvitz, H. R. dpl-1 DP and efl-1 E2F act with lin-35 Rb to antagonize Ras signaling in C. elegans vulval development. Mol. Cell 7, 461–473 (2001)

    Article  CAS  Google Scholar 

  4. Dynlacht, B. D., Brook, A., Dembski, M., Yenush, L. & Dyson, N. DNA-binding and trans-activation properties of Drosophila E2F and DP proteins. Proc. Natl Acad. Sci. USA 91, 6359–6363 (1994)

    Article  ADS  CAS  Google Scholar 

  5. Sawado, T. et al. dE2F2, a novel E2F-family transcription factor in Drosophila melanogaster . Biochem. Biophys. Res. Commun. 251, 409–415 (1998)

    Article  CAS  Google Scholar 

  6. DeGregori, J. & Johnson, D. G. Distinct and overlapping roles for E2F family members in transcription, proliferation and apoptosis. Curr. Mol. Med. 6, 739–748 (2006)

    CAS  PubMed  Google Scholar 

  7. Helin, K. et al. A cDNA encoding a pRB-binding protein with properties of the transcription factor E2F. Cell 70, 337–350 (1992)

    Article  CAS  Google Scholar 

  8. Wu, L. et al. The E2F1–3 transcription factors are essential for cellular proliferation. Nature 414, 457–462 (2001)

    Article  ADS  CAS  Google Scholar 

  9. Humbert, P. O. et al. E2f3 is critical for normal cellular proliferation. Genes Dev. 14, 690–703 (2000)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Leone, G. et al. Identification of a novel E2F3 product suggests a mechanism for determining specificity of repression by Rb proteins. Mol. Cell. Biol. 20, 3626–3632 (2000)

    Article  CAS  Google Scholar 

  11. Li, J. et al. Synergistic function of E2F7 and E2F8 is essential for cell survival and embryonic development. Dev. Cell 14, 62–75 (2008)

    Article  CAS  Google Scholar 

  12. Giangrande, P. H. et al. A role for E2F6 in distinguishing G1/S- and G2/M-specific transcription. Genes Dev. 18, 2941–2951 (2004)

    Article  CAS  Google Scholar 

  13. Cloud, J. E. et al. Mutant mouse models reveal the relative roles of E2F1 and E2F3 in vivo . Mol. Cell. Biol. 22, 2663–2672 (2002)

    Article  CAS  Google Scholar 

  14. Gaubatz, S. et al. E2F4 and E2F5 play an essential role in pocket protein-mediated G1 control. Mol. Cell 6, 729–735 (2000)

    Article  CAS  Google Scholar 

  15. Yamasaki, L. et al. Tumor induction and tissue atrophy in mice lacking E2F–1. Cell 85, 537–548 (1996)

    Article  CAS  Google Scholar 

  16. Murga, M. et al. Mutation of E2F2 in mice causes enhanced T lymphocyte proliferation, leading to the development of autoimmunity. Immunity 15, 959–970 (2001)

    Article  CAS  Google Scholar 

  17. Field, S. J. et al. E2F-1 functions in mice to promote apoptosis and suppress proliferation. Cell 85, 549–561 (1996)

    Article  CAS  Google Scholar 

  18. Zhu, J. W. et al. E2F1 and E2F2 determine thresholds for antigen-induced T-cell proliferation and suppress tumorigenesis. Mol. Cell. Biol. 21, 8547–8564 (2001)

    Article  CAS  Google Scholar 

  19. Li, F. X., Zhu, J. W., Hogan, C. J. & DeGregori, J. Defective gene expression, S phase progression, and maturation during hematopoiesis in E2F1/E2F2 mutant mice. Mol. Cell. Biol. 23, 3607–3622 (2003)

    Article  CAS  Google Scholar 

  20. Opavsky, R. et al. Specific tumor suppressor function for E2F2 in Myc-induced T cell lymphomagenesis. Proc. Natl Acad. Sci. USA 104, 15400–15405 (2007)

    Article  ADS  CAS  Google Scholar 

  21. Dirlam, A., Spike, B. T. & Macleod, K. F. Deregulated E2f-2 underlies cell cycle and maturation defects in retinoblastoma null erythroblasts. Mol. Cell. Biol. 27, 8713–8728 (2007)

    Article  CAS  Google Scholar 

  22. Parisi, T. et al. Selective requirements for E2f3 in the development and tumorigenicity of Rb-deficient chimeric tissues. Mol. Cell. Biol. 27, 2283–2293 (2007)

    Article  CAS  Google Scholar 

  23. Blais, A. & Dynlacht, B. D. E2F-associated chromatin modifiers and cell cycle control. Curr. Opin. Cell Biol. 19, 658–662 (2007)

    Article  CAS  Google Scholar 

  24. Giangrande, P. H., Hallstrom, T. C., Tunyaplin, C., Calame, K. & Nevins, J. R. Identification of E-box factor TFE3 as a functional partner for the E2F3 transcription factor. Mol. Cell. Biol. 23, 3707–3720 (2003)

    Article  CAS  Google Scholar 

  25. Schlisio, S., Halperin, T., Vidal, M. & Nevins, J. R. Interaction of YY1 with E2Fs, mediated by RYBP, provides a mechanism for specificity of E2F function. EMBO J. 21, 5775–5786 (2002)

    Article  CAS  Google Scholar 

  26. Jandacek, R. J., Heubi, J. E. & Tso, P. A novel, noninvasive method for the measurement of intestinal fat absorption. Gastroenterology 127, 139–144 (2004)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

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.

Author information

Author notes

  1. Lizhao Wu

    Present address: Present address: Department of Cell Biology and Molecular Medicine and University Hospital Cancer Center, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103, USA.,

  2. Shih-Yin Tsai, Rene Opavsky and Nidhi Sharma: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Genetics, College of Biological Sciences,

    Shih-Yin Tsai, Rene Opavsky, Nidhi Sharma, Lizhao Wu, Eric Nolan, Enrique Feria-Arias, Cynthia Timmers, Jana Opavska, Alain de Bruin, Jean-Leon Chong, Prashant Trikha & Gustavo Leone

  2. Human Cancer Genetics Program, Comprehensive Cancer Center,,

    Shih-Yin Tsai, Rene Opavsky, Nidhi Sharma, Lizhao Wu, Shan Naidu, Eric Nolan, Enrique Feria-Arias, Cynthia Timmers, Jana Opavska, Alain de Bruin, Jean-Leon Chong, Prashant Trikha & Gustavo Leone

  3. Department of Molecular Virology Immunology and Medical Genetics, College of Medicine,

    Shih-Yin Tsai, Rene Opavsky, Nidhi Sharma, Lizhao Wu, Shan Naidu, Eric Nolan, Enrique Feria-Arias, Cynthia Timmers, Jana Opavska, Alain de Bruin, Jean-Leon Chong, Prashant Trikha & Gustavo Leone

  4. Department of Veterinary Biosciences, College of Veterinary Medicine, and,

    Shan Naidu, Paul Stromberg & Thomas J. Rosol

  5. Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA ,

    Soledad A. Fernandez

Authors
  1. Shih-Yin Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rene Opavsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nidhi Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lizhao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shan Naidu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eric Nolan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Enrique Feria-Arias
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cynthia Timmers
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Jana Opavska
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Alain de Bruin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jean-Leon Chong
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Prashant Trikha
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Soledad A. Fernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Paul Stromberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Thomas J. Rosol
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Gustavo Leone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gustavo Leone.

Supplementary information

Supplementary Figures

The file contains Supplementary Figures 1-6 with Legends. (PDF 529 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07066

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing