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1.  E2F1-3 Switch from Activators in Progenitor Cells to Repressors in Differentiating Cells 
Nature  2009;462(7275):930-934.
In the classic paradigm of mammalian cell cycle control, Rb functions to restrict cells from entering S phase by sequestering E2F activators (E2f1, E2f2 and E2f3), which are invariably portrayed as the ultimate effectors of a transcriptional program that commit cells to enter and progress through S phase1, 2. Using a panel of tissue-specific cre-transgenic mice and conditional E2f alleles we examine the effects of E2f1, E2f2 and E2f3 triple deficiency in murine ES cells, embryos and small intestines. We show that in normal dividing progenitor cells E2F1-3 function as transcriptional activators, but contrary to current dogma, are dispensable for cell division and instead are necessary for cell survival. In differentiating cells they function in complex with Rb as repressors to silence E2F targets and facilitate exit from the cell cycle. The inactivation of Rb in differentiating cells resulted in a switch of E2F1-3 from repressors to activators, leading to the superactivation of E2F responsive targets and ectopic cell divisions, and loss of E2f1-3 completely suppressed these phenotypes. This work contextualizes the activator versus repressor functions of E2F1-3 in vivo, revealing distinct roles in dividing versus differentiating cells and in normal versus cancer-like cell cycles in vivo.
doi:10.1038/nature08677
PMCID: PMC2806193  PMID: 20016602
Small intestine; cell cycle; E2F; retinoblastoma; tumor suppressor
2.  Division and apoptosis in the E2f-deficient retina 
Nature  2009;462(7275):925.
E2fs 1-3, also known as activating E2fs, are viewed broadly as critical positive cell cycle regulators. They induce transcription and can drive cells out of quiescence. In flies and mammalian fibroblasts removing activating E2fs causes cell cycle arrest, suggesting an obligate proliferative role 1, 2. However, arrest is indirect as it is alleviated by removing the repressive E2f, dE2f2, in flies, or the tumor suppressor p53 in fibroblasts 3–5. Whether activating E2fs are required for division in vivo is thus an area of lively debate 6. Activating E2fs are also well known pro-apoptotic factors, a defense against oncogenesis 7. In some contexts E2f1 limits irradiation-induced apoptosis 8, 9, but in flies this occurs through repression of hid and the mammalian equivalent, Smac/Diablo is induced not repressed by E2f1 10, and in keratinoctyes it occurs indirectly through induction of DNA repair targets 11. Thus, a direct pro-survival function for activating E2fs in mammals has not been established. To address E2f1-3 function in vivo we focused on the mouse retina, a relatively simple CNS component that can be manipulated without compromising viability and has provided considerable insight into development and cancer 12–14. Here, we show that E2f1-3-deficient retinal progenitor cells or activated Muller glia divide. In the absence of activating E2fs, the Myc family drives proliferation. However, down-regulation of Sirt1, a p53 deacetylase, leads to hyperacetylation of p53 and cell death. Thus, activating E2fs are not universally required for mammalian cell division, but have an unexpected prosurvival role in development.
doi:10.1038/nature08544
PMCID: PMC2813224  PMID: 20016601
E2f; Neurogenesis; p21Cip1; p57Kip2; Histone deacetylase; Sirtuin; p53; Resveratrol
3.  Unique Requirement for Rb/E2F3 in Neuronal Migration: Evidence for Cell Cycle-Independent Functions▿  
Molecular and Cellular Biology  2007;27(13):4825-4843.
The cell cycle regulatory retinoblastoma (Rb) protein is a key regulator of neural precursor proliferation; however, its role has been expanded to include a novel cell-autonomous role in mediating neuronal migration. We sought to determine the Rb-interacting factors that mediate both the cell cycle and migration defects. E2F1 and E2F3 are likely Rb-interacting candidates that we have shown to be deregulated in the absence of Rb. Using mice with compound null mutations of Rb and E2F1 or E2F3, we asked to what extent either E2F1 or E2F3 interacts with Rb in neurogenesis. Here, we report that E2F1 and E2F3 are both functionally relevant targets in neural precursor proliferation, cell cycle exit, and laminar patterning. Each also partially mediates the Rb requirement for neuronal survival. Neuronal migration, however, is specifically mediated through E2F3, beyond its role in cell cycle regulation. This study not only outlines overlapping and distinct functions for E2Fs in neurogenesis but also is the first to establish a physiologically relevant role for the Rb/E2F pathway beyond cell cycle regulation in vivo.
doi:10.1128/MCB.02100-06
PMCID: PMC1951492  PMID: 17452454
4.  Rb-Mediated Neuronal Differentiation through Cell-Cycle–Independent Regulation of E2f3a 
PLoS Biology  2007;5(7):e179.
It has long been known that loss of the retinoblastoma protein (Rb) perturbs neural differentiation, but the underlying mechanism has never been solved. Rb absence impairs cell cycle exit and triggers death of some neurons, so differentiation defects may well be indirect. Indeed, we show that abnormalities in both differentiation and light-evoked electrophysiological responses in Rb-deficient retinal cells are rescued when ectopic division and apoptosis are blocked specifically by deleting E2f transcription factor (E2f) 1. However, comprehensive cell-type analysis of the rescued double-null retina exposed cell-cycle–independent differentiation defects specifically in starburst amacrine cells (SACs), cholinergic interneurons critical in direction selectivity and developmentally important rhythmic bursts. Typically, Rb is thought to block division by repressing E2fs, but to promote differentiation by potentiating tissue-specific factors. Remarkably, however, Rb promotes SAC differentiation by inhibiting E2f3 activity. Two E2f3 isoforms exist, and we find both in the developing retina, although intriguingly they show distinct subcellular distribution. E2f3b is thought to mediate Rb function in quiescent cells. However, in what is to our knowledge the first work to dissect E2f isoform function in vivo we show that Rb promotes SAC differentiation through E2f3a. These data reveal a mechanism through which Rb regulates neural differentiation directly, and, unexpectedly, it involves inhibition of E2f3a, not potentiation of tissue-specific factors.
Author Summary
The retinoblastoma protein (Rb), an important tumor suppressor, blocks division and death by inhibiting the E2f transcription factor family. In contrast, Rb is thought to promote differentiation by potentiating tissue-specific transcription factors, although differentiation defects in Rb null cells could be an indirect consequence of E2f-driven division and death. Here, we resolve different mechanisms by which Rb controls division, death, and differentiation in the retina. Removing E2f1 rescues aberrant division of differentiating Rb-deficient retinal neurons, as well as death in cells prone to apoptosis, and restores both normal differentiation and function of major cell types, such as photoreceptors. However, Rb-deficient starburst amacrine neurons differentiate abnormally even when E2f1 is removed, providing an unequivocal example of a direct role for Rb in neuronal differentiation. Rather than potentiating a cell-specific factor, Rb promotes starburst cell differentiation by inhibiting another E2f, E2f3a. This cell-cycle–independent activity broadens the importance of the Rb–E2f pathway, and suggests we should reassess its role in the differentiation of other cell types.
The retinoblastoma protein (Rb), a tumor suppressor, promotes the differentiation of starburst amacrine cells in the retina by inhibiting the transcription factor E2f3a, whereas it suppresses retinal cell division and death by inhibiting E2f1.
doi:10.1371/journal.pbio.0050179
PMCID: PMC1914394  PMID: 17608565

Results 1-4 (4)