The RB family is required for the self-renewal and survival of human embryonic stem cells

Conklin, Jamie F.; Baker, Julie C.; Sage, Julien

doi:10.1038/ncomms2254

Cited by 76 publications

(76 citation statements)

References 57 publications

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“…Phosphorylation of RB proteins by cyclin-CDK complexes in mouse and human ES cells was previously demonstrated to inhibit RB/E2F interaction with consequent effects on gene expression and cell proliferation (25,26,43,56). In this study we report that early steps during developmental regulation of the RB family in ES cells are additionally rendered through governance of subcellular localization.…”

Section: Discussionmentioning

confidence: 52%

The Evolutionarily Conserved C-terminal Domains in the Mammalian Retinoblastoma Tumor Suppressor Family Serve as Dual Regulators of Protein Stability and Transcriptional Potency

Sengupta¹,

Lingnurkar²,

Carey³

et al. 2015

Journal of Biological Chemistry

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Background: RB family protein abundance is dynamic and sensitive to growth conditions. Results: RB family turnover is mediated by C-terminal degrons in a process that is phosphorylation-sensitive. Conclusion: The RB family degrons are important regulatory domains linking stability and transcriptional potency. Significance: Dual control of stability and potency by RB family degrons may contribute to embryonic development.

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Section: Discussionmentioning

confidence: 52%

The Evolutionarily Conserved C-terminal Domains in the Mammalian Retinoblastoma Tumor Suppressor Family Serve as Dual Regulators of Protein Stability and Transcriptional Potency

Sengupta¹,

Lingnurkar²,

Carey³

et al. 2015

Journal of Biological Chemistry

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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. However, the function of RB function in human development is still a mystery.…”

Section: Discussionmentioning

confidence: 99%

“…The RB family of proteins have been described as critical factors for the self-renewal and survival of human ESCs (Conklin et al, 2012). Given that human cerebral organoids are very heterogeneous and complex, to examine the role of RB in a more homogenous population of NSCs, we induced the differentiation of wild-type and KO-ESCs into NSCs ('neurospheres') (Zhang et al, 2001) (Fig.…”

Section: Loss Of Rb Augments Proliferation Of Nscs In Vitromentioning

confidence: 99%

“…As human brains have a marked expansion of cerebral cortex with a unique outer subventricular zone compared with rodents (Hoerder-Suabedissen and Molnár, 2015;Kelava and Lancaster, 2016;Hansen et al, 2010), RB may affect human brain development in a different manner than it has been described in mice. Although the inactivation of RB family proteins causes G2/M arrest and cell death in human embryonic stem cells (ESCs) (Conklin et al, 2012), little is known about the role of RB during human brain development. In the past, ethical considerations and challenges in obtaining human samples have hampered the expansion of knowledge of human brain development.…”

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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“…Cdkn1a (also known as p21, encoding P21) is an inhibitor of the cyclin E-Cdk2 complex (Wang et al, 2008). Furthermore, retinoblastoma (RB) family proteins bind and repress the E2F family of transcription factor to restrict the G1/S transition (Conklin et al, 2012). mESCs themselves also express functional receptors associated with anesthetics such as GABA, NMDA, opioid, and adrenergic receptors (Kim et al, 2006;Andäng et al, 2008;Kim et al, 2008;Schwirtlich et al, 2010;Akeju et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Effects of prolonged anesthesia with dexmedetomidine, fentanyl, or remifentanil on the self-renewal of mouse embryonic stem cells

Cai

et al. 2015

Genet. Mol. Res.

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ABSTRACT. Previous study has indicated that exposure to anesthesia in early development leads to neuro-apoptosis and is followed by longterm cognitive dysfunction. Given that larger numbers of pregnant women currently receive anesthesia during the first trimester, we wanted to mimic this process in vitro using mouse embryonic stem cells (mESCs) and to explore how different anesthetics affect the self-renewal of mESCs. In the present study, mESCs were exposed to dexmedetomidine, fentanyl, or remifentanil at clinical concentrations for 48 h. The mESCs were then analyzed for cell proliferation and apoptosis. Furthermore, we used flow cytometry to analyze the cell cycle and quantitative real-time polymerase chain reaction to detect the gene expression during the cell cycle as well as the relevant stemness markers. We found that prolonged anesthesia with dexmedetomidine or fentanyl significantly inhibited mESC proliferation, with fewer cell numbers as well as decreased expression of cyclin B and cyclin E mRNA compared to that in the control group; meanwhile, p21 and RB2 gene expression was increased. Additionally, increases or decreases in the proportion of cells in the G1 and S phases, respectively, were observed in the dexmedetomidine-and fentanyl-treated groups. These anesthetics also repressed the gene expression of mESC stemness makers such as Oct4 and Sox2. However, remifentanil seemed to have no significant influence on the self-renewal of mESCs. These results demonstrated that prolonged anesthesia with dexmedetomidine or fentanyl, but not remifentanil, inhibited mESC proliferation by blocking the G1 to S transition, and repressed the maintenance of mESC stemness.

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The RB family is required for the self-renewal and survival of human embryonic stem cells

Cited by 76 publications

References 57 publications

The Evolutionarily Conserved C-terminal Domains in the Mammalian Retinoblastoma Tumor Suppressor Family Serve as Dual Regulators of Protein Stability and Transcriptional Potency

The Evolutionarily Conserved C-terminal Domains in the Mammalian Retinoblastoma Tumor Suppressor Family Serve as Dual Regulators of Protein Stability and Transcriptional Potency

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

Effects of prolonged anesthesia with dexmedetomidine, fentanyl, or remifentanil on the self-renewal of mouse embryonic stem cells

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