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Division and apoptosis of E2f-deficient retinal progenitors

Nature volume 462, pages 925–929 (2009)Cite this article

Abstract

The activating E2f transcription factors (E2f1, E2f2 and E2f3) induce transcription and are widely viewed as essential positive cell cycle regulators. Indeed, they drive cells out of quiescence, and the ‘cancer cell cycle’ in Rb1 null cells is E2f-dependent1,2. Absence of activating E2fs in flies or mammalian fibroblasts causes cell cycle arrest3,4, but this block is alleviated by removing repressive E2f or the tumour suppressor p53, respectively5,6,7. Thus, whether activating E2fs are indispensable for normal division is an area of debate1. Activating E2fs are also well known pro-apoptotic factors, providing a defence against oncogenesis8, yet E2f1 can limit irradiation-induced apoptosis9,10. In flies this occurs through repression of hid (also called Wrinkled; Smac/Diablo in mammals). However, in mammals the mechanism is unclear because Smac/Diablo is induced, not repressed, by E2f111, and in keratinocytes survival is promoted indirectly through induction of DNA repair targets12. Thus, a direct pro-survival function for E2f1–3 and/or its relevance beyond irradiation has not been established. To address E2f1–3 function in normal cells in vivo we focused on the mouse retina, which is a relatively simple central nervous system component that can be manipulated genetically without compromising viability and has provided considerable insight into development and cancer2,13. Here we show that unlike fibroblasts, E2f1–3 null retinal progenitor cells or activated Müller glia can divide. We attribute this effect to functional interchangeability with Mycn. However, loss of activating E2fs caused downregulation of the p53 deacetylase Sirt1, p53 hyperacetylation and elevated apoptosis, establishing a novel E2f–Sirt1–p53 survival axis in vivo. Thus, activating E2fs are not universally required for normal mammalian cell division, but have an unexpected pro-survival role in development.

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Figure 1: Mycn allows division without activating E2fs.
Figure 2: Mycn blocks Cdk inhibitor induction in E2f1–3 null progenitors.
Figure 3: A pro-survival role for activating E2fs.
Figure 4: E2fs promote survival through Sirt1-mediated p53 deacetylation.

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Acknowledgements

We thank L. van Parijs and R. Weinberg for plasmids; R. Eisenman for mice; L. Penn for advice on Myc; and M. Cayouette and J. Wrana for comments. This work was supported by a grant from the Canadian Institutes for Health Research to R.B. (MOP-74570).

Author Contributions D.C. and R.B. designed the study and interpreted data. D.C. performed all the experiments and was aided in viral and electroporation assays by M.P. P.W., G.L. and P.S.K. provided reagents including mice. R.B. wrote the paper and all authors contributed to editing.

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Authors and Affiliations

  1. Departments of Ophthalmology and Visual Science, Toronto Western Research Institute, University Health Network, and Laboratory Medicine and Pathobiology, University of Toronto, Ontario M5T 2S8, Canada

    Danian Chen, Marek Pacal & Rod Bremner

  2. Department of Molecular Virology, and Department of Molecular Genetics, Human Cancer Genetics Program, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, USA,

    Pamela Wenzel & Gustavo Leone

  3. Departments of Cell Biology and Human Anatomy University of California Davis School of Medicine, Davis, California 95616, USA,

    Paul S. Knoepfler

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Correspondence to Rod Bremner.

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Chen, D., Pacal, M., Wenzel, P. et al. Division and apoptosis of E2f-deficient retinal progenitors. Nature 462, 925–929 (2009). https://doi.org/10.1038/nature08544

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