Rb-Mediated Neuronal Differentiation through Cell-Cycle–Independent Regulation of E2f3a

Chen, Danian; Opavský, René; Pacal, Marek; Tanimoto, Naoyuki; Wenzel, Pamela L.; Seeliger, Mathias W.; Leone, Gustavo; Bremner, Rod

doi:10.1371/journal.pbio.0050179

Cited by 79 publications

(122 citation statements)

References 72 publications

Supporting

Mentioning

111

Contrasting

Order By: Relevance

“…5,6,8,9,17,18,[41][42][43] Thus through our identification of E2f3&4-bound promoters in NPCs, we have significantly expanded our understanding of how cell cycle regulators can direct cell fate control. While this study provides a number of important insights, we offer two key conceptual findings: E2f transcription factors are poised as widespread regulators of cell fate-associated genes in NPCs, establishing a pervasive direct role for the cell cycle machinery Figure 4 E2f3 and Ctcf are co-enriched at nervous system-related genes.…”

Section: Discussionmentioning

confidence: 99%

“…Cell cycle dynamics strongly influence neural precursor cell (NPC) maintenance and neurogenesis, [1][2][3][4] and gain-or loss-of-function studies have demonstrated key roles for cell cycle proteins, including the E2f family, in NPC fate decisions. [3][4][5][6][7][8][9][10][11][12][13][14][15][16] E2f3 is required for proper cortical migration of neurons and to maintain the balance between NPC self-renewal, proliferation and differentiation, and its loss disrupts long-term neurogenesis and cortical function; E2f1 deficiency impairs NPC proliferation, and E2f4 deficiency leads to inhibition of NPC self-renewal and severe defects in telencephalic development. 6,[8][9][10]17 A pivotal question is whether cell fate control by the pRb/E2f pathway is largely a consequence of cell cycle regulation, or due to direct regulation of cell fate-associated genes.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Tissue-specific targeting of cell fate regulatory genes by E2f factors

et al. 2015

View full text Add to dashboard Cite

Cell cycle proteins are important regulators of diverse cell fate decisions, and in this capacity have pivotal roles in neurogenesis and brain development. The mechanisms by which cell cycle regulation is integrated with cell fate control in the brain and other tissues are poorly understood, and an outstanding question is whether the cell cycle machinery regulates fate decisions directly or instead as a secondary consequence of proliferative control. Identification of the genes targeted by E2 promoter binding factor (E2f) transcription factors, effectors of the pRb/E2f cell cycle pathway, will provide essential insights into these mechanisms. We identified the promoter regions bound by three neurogenic E2f factors in neural precursor cells in a genome-wide manner. Through bioinformatic analyses and integration of published genomic data sets we uncovered hundreds of transcriptionally active E2f-bound promoters corresponding to genes that control cell fate processes, including key transcriptional regulators and members of the Notch, fibroblast growth factor, Wnt and Tgf-β signaling pathways. We also demonstrate a striking enrichment of the CCCTC binding factor transcription factor (Ctcf) at E2f3-bound nervous system-related genes, suggesting a potential regulatory co-factor for E2f3 in controlling differentiation. Finally, we provide the first demonstration of extensive tissue specificity among E2f target genes in mammalian cells, whereby E2f3 promoter binding is well conserved between neural and muscle precursors at genes associated with cell cycle processes, but is tissue-specific at differentiation-associated genes. Our findings implicate the cell cycle pathway as a widespread regulator of cell fate genes, and suggest that E2f3 proteins control cell typespecific differentiation programs by regulating unique sets of target genes. This work significantly enhances our understanding of how the cell cycle machinery impacts cell fate and differentiation, and will importantly drive further discovery regarding the mechanisms of cell fate control and transcriptional regulation in the brain, as well as in other tissues.

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Tissue-specific targeting of cell fate regulatory genes by E2f factors

et al. 2015

View full text Add to dashboard Cite

show abstract

“…E2F1 is released and activated upon Rb phosphorylation and is known to contribute to apoptosis in Parkinson disease (8) and stroke (13). Moreover, Rb null rod photoreceptors undergo E2F1-dependent apoptosis (15), and either directed expression of E2f1 in these cells (19) or inhibition of pRb through T-antigen expression also leads to cell death. Thus, we next asked whether E2Fs contribute to Rd1 photoreceptor degeneration.…”

Section: Interference With Cdk Function Reduces Apoptosis In Rd1 Retinalmentioning

confidence: 99%

“…For example, in the developing retina, retinoblastoma protein (Rb) is required to couple terminal differentiation to cell cycle exit, and thus its absence leads to E2F1-dependent ectopic division (15). In dividing cells, Rb is inactivated by CDK4-or CDK6-mediated phosphorylation, which inhibits its binding to E2F1 (reviewed in ref.…”

mentioning

confidence: 99%

Retinal degeneration depends on Bmi1 function and reactivation of cell cycle proteins

Zencak

Schouwey

Chen

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The epigenetic regulator Bmi1 controls proliferation in many organs. Reexpression of cell cycle proteins such as cyclin-dependent kinases (CDKs) is a hallmark of neuronal apoptosis in neurodegenerative diseases. Here we address the potential role of Bmi1 as a key regulator of cell cycle proteins during neuronal apoptosis. We show that several cell cycle proteins are expressed in different models of retinal degeneration and required in the Rd1 photoreceptor death process. Deleting E2f1, a downstream target of CDKs, provided temporary protection in Rd1 mice. Most importantly, genetic ablation of Bmi1 provided extensive photoreceptor survival and improvement of retinal function in Rd1 mice, mediated by a decrease in cell cycle markers and regulators independent of p16 Ink4a and p19 Arf . These data reveal that Bmi1 controls the cell cycle-related death process, highlighting this pathway as a promising therapeutic target for neuroprotection in retinal dystrophies.blindness | neurodegeneration | polycomb

show abstract

“…During terminal differentiation of cones, thyroid hormone receptor TR␤2 is required for M opsin induction such that without TR␤2, cones express only S opsin (5). Factors that promote rod differentiation and survival include leucine zipper protein Nrl (6), orphan nuclear receptor Nr2e3 (7, 8), homeodomain proteins Crx and Otx2 (9-11), and retinoblastoma protein Rb (12,13). Nrl induces Nr2e3 expression and these two genes define a transcriptional hierarchy for rod differentiation.…”

mentioning

confidence: 99%

Retinoid-related orphan nuclear receptor RORβ is an early-acting factor in rod photoreceptor development

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

110

105

View full text Add to dashboard Cite

Rods and cones are morphologically and developmentally distinct photoreceptor types with different functions in vision. Cones mediate daylight and color vision and in most mammals express M and S opsin photopigments for sensitivity to medium-long and short light wavelengths, respectively. Rods mediate dim light vision and express rhodopsin photopigment. The transcription factor networks that direct differentiation of each photoreceptor type are incompletely defined. Here, we report that Rorb ؊/؊ mice lacking retinoid-related orphan nuclear receptor ␤ lose rods but overproduce primitive S cones that lack outer segments. The phenotype reflects pronounced plasticity between rod and cone lineages and resembles that described for Nrl ؊/؊ mice lacking neural retina leucine zipper factor. Rorb ؊/؊ mice lack Nrl expression and reexpression of Nrl in Rorb ؊/؊ mice converts cones to rod-like cells. Thus, Rorb directs rod development and does so at least in part by inducing the Nrl-mediated pathway of rod differentiation.cone ͉ differentiation R ods and cones are distinct receptor cell types that mediate dim and bright light vision, respectively. In the mouse, cones are generated between midgestation and birth (1) and subpopulations differentially express M and S opsin photopigments for sensitivity to medium-long and short light wavelengths, respectively (2). Rods express rhodopsin and greatly outnumber cones in mice. Rod generation lags behind that of cones and is more protracted, lasting until about a week after birth. Rods, cones, and other retinal cell types are generated in a stereotypical order from multipotent progenitors, and it has been proposed that a combination of transcription factor activities and external signals at a given developmental stage prompts progenitors to enter specific differentiation pathways (3, 4).The transcription factors that direct the generation of rod and cone precursors and the terminal differentiation of these cell types are incompletely defined. During terminal differentiation of cones, thyroid hormone receptor TR␤2 is required for M opsin induction such that without TR␤2, cones express only S opsin (5). Factors that promote rod differentiation and survival include leucine zipper protein Nrl (6), orphan nuclear receptor Nr2e3 (7, 8), homeodomain proteins Crx and Otx2 (9-11), and retinoblastoma protein Rb (12,13). Nrl induces Nr2e3 expression and these two genes define a transcriptional hierarchy for rod differentiation. Nrl Ϫ/Ϫ mice overproduce S cones at the expense of rods (6) whereas ectopic Nrl expression converts cones to rods (14). Nr2e3 deficiency causes an enhanced cone phenotype and misexpression of cone genes in rods, suggesting that Nr2e3 represses cone genes to maintain the rod phenotype (15-19). Human NRL and NR2E3 mutations result in retinopathy phenotypes (8,20). The above findings suggest that rod and cone precursors share a default differentiation program as cones and that rod differentiation requires the action of additional transcription factors.The Rorb gene encodin...

show abstract

Rb-Mediated Neuronal Differentiation through Cell-Cycle–Independent Regulation of E2f3a

Cited by 79 publications

References 72 publications

Tissue-specific targeting of cell fate regulatory genes by E2f factors

Tissue-specific targeting of cell fate regulatory genes by E2f factors

Retinal degeneration depends on Bmi1 function and reactivation of cell cycle proteins

Retinoid-related orphan nuclear receptor RORβ is an early-acting factor in rod photoreceptor development

Contact Info

Product

Resources

About