The Rb/E2F Pathway Modulates Neurogenesis through Direct Regulation of the Dlx1/Dlx2 Bigene Cluster

Ghanem, Noël; Andrusiak, Matthew G.; Svoboda, Devon S.; Lafi, Sawsan M. Al; Julian, Lisa M.; McClellan, Kelly A.; Repentigny, Yves De; Kothary, Rashmi; Ekker, Marc; Blais, Alexandre; Park, David; Slack, Ruth S.

doi:10.1523/jneurosci.1344-12.2012

Cited by 45 publications

(48 citation statements)

References 52 publications

(72 reference statements)

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“…Moreover, KO mouse models have revealed the role of RB during neuronal differentiation and migration, as well as in the regulation of cell death in the embryo and adult brain (Andrusiak et al, 2011;Ghanem et al, 2012;McClellan et al, 2007;Christie et al, 2014;Ferguson et al, 2005;Macleod et al, 1996;Vandenbosch et al, 2016;Yu et al, 2012). The finding that lack of the RB1 gene is associated with structural brain abnormalities in human (Mitter et al, 2011;Rodjan et al, 2010), and inactivation of RB family proteins affects cell cycle and cell death in human ESCs (Conklin et al, 2012), suggest that RB might have a role during human brain development.…”

Section: Discussionmentioning

confidence: 99%

“…As RB is also expressed in a subset of Tuj1 + neuronal cells and RB plays important roles during mouse neurogenesis (Ferguson et al, 2005;Ghanem et al, 2012;Naser et al, 2016), we also analyzed sections from 28 DIV wild-type and RB1-KO organoids stained for Tuj1. In both sets of organoids, Tuj1…”

Section: Rb Is Essential For Proper Neuronal Migration In Organoidsmentioning

confidence: 99%

“…Initially, RB was described as regulating the G1/S transition of the cell cycle through E2F-mediated transcriptional regulation in many tissues, including the nervous system (Classon and Harlow, 2002;McClellan and Slack, 2006;Julian et al, 2016;MacPherson et al, 2003;Naser et al, 2016). Recently, studies of brain-specific Rb1-KO mice revealed other roles of the Rb1 gene that extend beyond cell cycle control, such as regulation of neuronal differentiation and migration (Andrusiak et al, 2011;Ghanem et al, 2012;McClellan et al, 2007;Christie et al, 2014;Ferguson et al, 2005). Moreover, the lack of RB promotes apoptosis in some cell types, but not in others, through p53-dependent or -independent pathways (Macleod et al, 1996;Vandenbosch et al, 2016;Yu et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Retinoblastoma protein controls growth, survival and neuronal migration in human cerebral organoids

Matsui

Nieto-Esteìvez

Kyrychenko

et al. 2017

Journal of Cell Science

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The tumor suppressor retinoblastoma protein (RB) regulates S-phase cell cycle entry via E2F transcription factors. Knockout (KO) mice have shown that RB plays roles in cell migration, differentiation and apoptosis, in developing and adult brain. In addition, the RB family is required for self-renewal and survival of human embryonic stem cells (hESCs). Since little is known about the role of RB in human brain development, we investigated its function in cerebral organoids differentiated from gene-edited hESCs lacking RB. We show that RB is abundantly expressed in neural stem and progenitor cells in organoids at 15 and 28 days of culture. RB loss promoted S-phase entry in DCX + cells and increased apoptosis in Sox2 + neural stem and progenitor cells, and in DCX + and Tuj1 + neurons. Associated with these cell cycle and pro-apoptotic effects, we observed increased CCNA2 and BAX gene expression, respectively. Moreover, we observed aberrant Tuj1 + neuronal migration in RB-KO organoids and upregulation of the gene encoding VLDLR, a receptor important in reelin signaling. Corroborating the results in RB-KO organoids in vitro, we observed ectopically localized Tuj1 + cells in RB-KO teratomas grown in vivo. Taken together, these results identify crucial functions for RB in the cerebral organoid model of human brain development.

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Section: Discussionmentioning

confidence: 99%

Section: Rb Is Essential For Proper Neuronal Migration In Organoidsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Retinoblastoma protein controls growth, survival and neuronal migration in human cerebral organoids

Matsui

Nieto-Esteìvez

Kyrychenko

et al. 2017

Journal of Cell Science

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“…In addition, a number of key cell fate genes and pathways have been identified as E2f-regulated targets driving E2f-dependent fate decisions in NPCs. These include the neurogenesis and migration genes Dlx1/Dxl2 and Neo1 (Neogenin), 18,19 the growth factor fibroblast growth factor 2 (Fgf2), 17 the pluripotency and self-renewal factor Sox2, 8 and the Notch/Hes 11 and Sonic Hedgehog pathways. 10 Together, these findings demonstrate a direct role for pRb/E2f at cell fate-associated genes, but the extent of this interaction is unknown.…”

mentioning

confidence: 99%

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

et al. 2015

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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.

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“…As the first identified tumor suppressor gene [9], Rb is recognized to play a fundamental role in a signaling pathway that controls cell proliferation [10]. Rb regulates the transcription of genes that are essential for DNA replication and cell cycle progression by binding and inhibiting E2F transcription factors [11]. In the Rb-E2F pathway including negative feedback loops involving miR449, miR449 provides a twofold safety mechanism to avoid excessive E2F-induced proliferation by cell cycle arrest and apoptosis [12].…”

Section: Introductionmentioning

confidence: 99%

Bifurcations and Dynamics of the Rb-E2F Pathway Involving miR449

Shen¹

2017

Complexity

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We focused on the gene regulative network involving Rb-E2F pathway and microRNAs (miR449) and studied the influence of time delay on the dynamical behaviors of Rb-E2F pathway by using Hopf bifurcation theory. It is shown that under certain assumptions the steady state of the delay model is asymptotically stable for all delay values; there is a critical value under another set of conditions; the steady state is stable when the time delay is less than the critical value, while the steady state is changed to be unstable when the time delay is greater than the critical value. Thus, Hopf bifurcation appears at the steady state when the delay passes through the critical value. Numerical simulations were presented to illustrate the theoretical results.

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The Rb/E2F Pathway Modulates Neurogenesis through Direct Regulation of the Dlx1/Dlx2 Bigene Cluster

Cited by 45 publications

References 52 publications

Retinoblastoma protein controls growth, survival and neuronal migration in human cerebral organoids

Retinoblastoma protein controls growth, survival and neuronal migration in human cerebral organoids

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

Bifurcations and Dynamics of the Rb-E2F Pathway Involving miR449

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