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Ravi Kambadur - One of the best experts on this subject based on the ideXlab platform.
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myostatin signals through pax7 to regulate satellite Cell self renewal
Experimental Cell Research, 2008Co-Authors: Craig Mcfarlane, Alex Hennebry, Erin Plummer, Mark Thomas, Ravi Kambadur, Nicholas Ling, Mridula SharmaAbstract:Myostatin, a Transforming Growth Factor-beta (TGF-β) super-family member, has previously been shown to negatively regulate satellite Cell activation and Self-Renewal. However, to date the mechanism behind Myostatin function in satellite Cell biology is not known. Here we show that Myostatin signals via a Pax7-dependent mechanism to regulate satellite Cell Self-Renewal. While excess Myostatin inhibited Pax7 expression via ERK1/2 signaling, an increase in Pax7 expression was observed following both genetic inactivation and functional antagonism of Myostatin. As a result, we show that either blocking or inactivating Myostatin enhances the partitioning of the fusion-incompetent self-renewed satellite Cell lineage (high Pax7 expression, low MyoD expression) from the pool of actively proliferating myogenic precursor Cells. Consistent with this result, over-expression of Pax7 in C2C12 myogenic Cells resulted in increased Self-Renewal through a mechanism which slowed both myogenic proliferation and differentiation. Taken together, these results suggest that increased expression of Pax7 promotes satellite Cell Self-Renewal, and furthermore Myostatin may control the process of satellite Cell Self-Renewal through regulation of Pax7. Thus we speculate that, in addition to the intrinsic factors (such as Pax7), extrinsic factors both positive and negative in nature, will play a major role in determining the stemness of skeletal muscle satellite Cells.
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myostatin signals through pax7 to regulate satellite Cell self renewal
Experimental Cell Research, 2008Co-Authors: Craig Mcfarlane, Alex Hennebry, Erin Plummer, Mark Thomas, Ravi Kambadur, Nicholas Ling, Mridula SharmaAbstract:Myostatin, a Transforming Growth Factor-beta (TGF-β) super-family member, has previously been shown to negatively regulate satellite Cell activation and Self-Renewal. However, to date the mechanism behind Myostatin function in satellite Cell biology is not known. Here we show that Myostatin signals via a Pax7-dependent mechanism to regulate satellite Cell Self-Renewal. While excess Myostatin inhibited Pax7 expression via ERK1/2 signaling, an increase in Pax7 expression was observed following both genetic inactivation and functional antagonism of Myostatin. As a result, we show that either blocking or inactivating Myostatin enhances the partitioning of the fusion-incompetent self-renewed satellite Cell lineage (high Pax7 expression, low MyoD expression) from the pool of actively proliferating myogenic precursor Cells. Consistent with this result, over-expression of Pax7 in C2C12 myogenic Cells resulted in increased Self-Renewal through a mechanism which slowed both myogenic proliferation and differentiation. Taken together, these results suggest that increased expression of Pax7 promotes satellite Cell Self-Renewal, and furthermore Myostatin may control the process of satellite Cell Self-Renewal through regulation of Pax7. Thus we speculate that, in addition to the intrinsic factors (such as Pax7), extrinsic factors both positive and negative in nature, will play a major role in determining the stemness of skeletal muscle satellite Cells.
Sean J Morrison - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of Xie et al.: Sphingolipid Modulation Activates Proteostasis Programs to Govern Human Hematopoietic Stem Cell Self-Renewal
Cell stem cell, 2019Co-Authors: Sean J Morrison, Corbin E. MeachamAbstract:This article shows an example of the peer review process for "Sphingolipid Modulation Activates Proteostasis Programs to Govern Human Hematopoietic Stem Cell Self-Renewal" (Xie et al., 2019).
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Abstract SY13-04: Stem Cell Self-Renewal and cancer
Tumor Biology, 2014Co-Authors: Sean J MorrisonAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Haematopoietic stem Cell Self-Renewal and leukemogenesis “Pre-leukemic” mutations are thought to promote clonal expansion of haematopoietic stem Cells (HSCs) by increasing Self-Renewal and competitiveness; however, mutations that increase HSC proliferation tend to reduce competitiveness and Self-Renewal potential, raising the question of how a mutant HSC can sustainably outcompete wild-type HSCs. Activating mutations in NRAS are prevalent in human myeloproliferative neoplasms and leukemia. We found that a single allele of oncogenic NrasG12D increases HSC proliferation but also increases reconstituting and Self-Renewal potential upon serial transplantation in irradiated mice, all prior to leukemia initiation. NrasG12D also confers long-term Self-Renewal potential upon multipotent progenitors. To explore the mechanism by which NrasG12D promotes HSC proliferation and Self-Renewal we assessed Cell cycle kinetics using H2B-GFP label retention and BrdU incorporation. NrasG12D had a bimodal effect on HSCs, increasing the rate at which some HSCs divide and reducing the rate at which others divide. This mirrored bimodal effects on reconstituting potential as rarely dividing NrasG12D HSCs outcompeted wild-type HSCs while frequently dividing NrasG12D HSCs did not. NrasG12D had these effects by promoting STAT5 signaling, inducing different transcriptional responses in different subsets of HSCs. One signal can therefore increase HSC proliferation, competitiveness, and Self-Renewal through bimodal effects on HSC gene expression, cycling, and reconstituting potential. We have also developed methods for studying protein synthesis by individual stem Cells in vivo. Currently, there are almost no data on protein synthesis in any somatic stem Cell. We found that the amount of protein synthesized per hour in HSCs in vivo was lower than in most other haematopoietic Cells, even if we controlled for differences in Cell cycle status or forced HSCs to undergo self-renewing divisions. Reduced ribosomal function in Rpl24Bst/+ mice further reduced protein synthesis in HSCs and impaired HSC function. Pten deletion increased protein synthesis in HSCs but also reduced HSC function. Rpl24Bst/+ Cell-autonomously rescued the effects of Pten deletion in HSCs, blocking the increase in protein synthesis, restoring HSC function, and delaying leukemogenesis. Pten deficiency thus depletes HSCs and promotes leukemia partly by increasing protein synthesis. Increased or decreased protein synthesis impairs HSC function. Citation Format: Sean J. Morrison. Stem Cell Self-Renewal and cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr SY13-04. doi:10.1158/1538-7445.AM2014-SY13-04
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mechanisms of stem Cell self renewal
Annual Review of Cell and Developmental Biology, 2009Co-Authors: Shenghui He, Daisuke Nakada, Sean J MorrisonAbstract:Self-Renewal is the process by which stem Cells divide to make more stem Cells, perpetuating the stem Cell pool throughout life. Self-Renewal is division with maintenance of the undifferentiated state. This requires Cell cycle control and often maintenance of multipotency or pluripotency, depending on the stem Cell. Self-Renewal programs involve networks that balance proto-oncogenes (promoting Self-Renewal), gate-keeping tumor suppressors (limiting Self-Renewal), and care-taking tumor suppressors (maintaining genomic integrity). These Cell-intrinsic mechanisms are regulated by Cell-extrinsic signals from the niche, the microenvironment that maintains stem Cells and regulates their function in tissues. In response to changing tissue demands, stem Cells undergo changes in Cell cycle status and developmental potential over time, requiring different Self-Renewal programs at different stages of life. Reduced stem Cell function and tissue regenerative capacity during aging are caused by changes in Self-Renewal ...
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Mechanisms of stem Cell Self-Renewal.
Annual review of cell and developmental biology, 2009Co-Authors: Daisuke Nakada, Sean J MorrisonAbstract:Self-Renewal is the process by which stem Cells divide to make more stem Cells, perpetuating the stem Cell pool throughout life. Self-Renewal is division with maintenance of the undifferentiated state. This requires Cell cycle control and often maintenance of multipotency or pluripotency, depending on the stem Cell. Self-Renewal programs involve networks that balance proto-oncogenes (promoting Self-Renewal), gate-keeping tumor suppressors (limiting Self-Renewal), and care-taking tumor suppressors (maintaining genomic integrity). These Cell-intrinsic mechanisms are regulated by Cell-extrinsic signals from the niche, the microenvironment that maintains stem Cells and regulates their function in tissues. In response to changing tissue demands, stem Cells undergo changes in Cell cycle status and developmental potential over time, requiring different Self-Renewal programs at different stages of life. Reduced stem Cell function and tissue regenerative capacity during aging are caused by changes in Self-Renewal programs that augment tumor suppression. Cancer arises from mutations that inappropriately activate Self-Renewal programs.
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Stem Cell Self-Renewal and cancer Cell proliferation are regulated by common networks that balance the activation of proto-oncogenes and tumor suppressors.
Cold Spring Harbor symposia on quantitative biology, 2005Co-Authors: Ricardo Pardal, Anna V. Molofsky, Sean J MorrisonAbstract:Networks of proto-oncogenes and tumor suppressors that control cancer Cell proliferation also regulate stem Cell Self-Renewal and possibly stem Cell aging. Proto-oncogenes promote regenerative capacity by promoting stem Cell function but must be balanced with tumor suppressor activity to avoid neoplastic proliferation. Conversely, tumor suppressors inhibit regenerative capacity by promoting Cell death or senescence in stem Cells. For example, the polycomb family proto-oncogene, Bmi-1, is consistently required for the Self-Renewal of diverse adult stem Cells, as well as for the proliferation of cancer Cells in the same tissues. Bmi-1 promotes stem Cell Self-Renewal partly by repressing the expression of Ink4a and Arf, tumor suppressor genes that are commonly deleted in cancer. Despite ongoing Bmi-1 expression, Ink4a expression increases with age, potentially reducing stem Cell frequency and function. Increased tumor suppressor activity during aging therefore may partly account for age-related declines in stem Cell function. Thus, networks of proto-oncogenes and tumor suppressors have evolved to coordinately regulate stem Cell function throughout life. Imbalances within such networks cause cancer or premature declines in stem Cell activity that resemble accelerated aging.
Stephen Dalton - One of the best experts on this subject based on the ideXlab platform.
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lif stat3 controls es Cell self renewal and pluripotency by a myc dependent mechanism
Development, 2005Co-Authors: Peter Cartwright, Cameron Mclean, Allan Sheppard, Duane Rivett, Karen Louise Jones, Stephen DaltonAbstract:Murine ES Cells can be maintained as a pluripotent, self-renewing population by LIF/STAT3-dependent signaling. The downstream effectors of this pathway have not been previously defined. In this report, we identify a key target of the LIF Self-Renewal pathway by showing that STAT3 directly regulates the expression of the Myc transcription factor. Murine ES Cells express elevated levels of Myc and following LIF withdrawal, Myc mRNA levels collapse and Myc protein becomes phosphorylated on threonine 58 (T58), triggering its GSK3beta dependent degradation. Maintained expression of stable Myc (T58A) renders Self-Renewal and maintenance of pluripotency independent of LIF. By contrast, expression of a dominant negative form of Myc antagonizes Self-Renewal and promotes differentiation. Transcriptional control by STAT3 and suppression of T58 phosphorylation are crucial for regulation of Myc activity in ES Cells and therefore in promoting Self-Renewal. Together, our results establish a mechanism for how LIF and STAT3 regulate ES Cell Self-Renewal and pluripotency.
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lif stat3 controls es Cell self renewal and pluripotency by a myc dependent mechanism
Development, 2005Co-Authors: Peter Cartwright, Cameron Mclean, Allan Sheppard, Duane Rivett, Karen Louise Jones, Stephen DaltonAbstract:Murine ES Cells can be maintained as a pluripotent, self-renewing population by LIF/STAT3-dependent signaling. The downstream effectors of this pathway have not been previously defined. In this report, we identify a key target of the LIF Self-Renewal pathway by showing that STAT3 directly regulates the expression of the Myc transcription factor. Murine ES Cells express elevated levels of Myc and following LIF withdrawal, Myc mRNA levels collapse and Myc protein becomes phosphorylated on threonine 58 (T58), triggering its GSK3β dependent degradation. Maintained expression of stable Myc (T58A) renders Self-Renewal and maintenance of pluripotency independent of LIF. By contrast, expression of a dominant negative form of Myc antagonizes Self-Renewal and promotes differentiation. Transcriptional control by STAT3 and suppression of T58 phosphorylation are crucial for regulation of Myc activity in ES Cells and therefore in promoting Self-Renewal. Together, our results establish a mechanism for how LIF and STAT3 regulate ES Cell Self-Renewal and pluripotency.
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LIF/STAT3 controls ES Cell Self-Renewal and pluripotency by a Myc-dependent mechanism.
Development (Cambridge England), 2005Co-Authors: Peter Cartwright, Cameron Mclean, Allan Sheppard, Duane Rivett, Karen Louise Jones, Stephen DaltonAbstract:Murine ES Cells can be maintained as a pluripotent, self-renewing population by LIF/STAT3-dependent signaling. The downstream effectors of this pathway have not been previously defined. In this report, we identify a key target of the LIF Self-Renewal pathway by showing that STAT3 directly regulates the expression of the Myc transcription factor. Murine ES Cells express elevated levels of Myc and following LIF withdrawal, Myc mRNA levels collapse and Myc protein becomes phosphorylated on threonine 58 (T58), triggering its GSK3beta dependent degradation. Maintained expression of stable Myc (T58A) renders Self-Renewal and maintenance of pluripotency independent of LIF. By contrast, expression of a dominant negative form of Myc antagonizes Self-Renewal and promotes differentiation. Transcriptional control by STAT3 and suppression of T58 phosphorylation are crucial for regulation of Myc activity in ES Cells and therefore in promoting Self-Renewal. Together, our results establish a mechanism for how LIF and STAT3 regulate ES Cell Self-Renewal and pluripotency.
Melanie J Welham - One of the best experts on this subject based on the ideXlab platform.
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regulation of embryonic stem Cell self renewal by phosphoinositide 3 kinase dependent signaling
Journal of Biological Chemistry, 2004Co-Authors: Nicholas R D Paling, Helen Wheadon, Heather K Bone, Melanie J WelhamAbstract:Abstract The maintenance of murine embryonic stem (ES) Cell Self-Renewal is regulated by leukemia inhibitory factor (LIF)-dependent activation of signal transducer and activator of transcription 3 (STAT3) and LIF-independent mechanisms including Nanog, BMP2/4, and Wnt signaling. Here we demonstrate a previously undescribed role for phosphoinositide 3-kinases (PI3Ks) in regulation of murine ES Cell Self-Renewal. Treatment with the reversible PI3K inhibitor, LY294002, or more specific inhibition of class IA PI3K via regulated expression of dominant negative Δp85, led to a reduction in the ability of LIF to maintain Self-Renewal, with Cells concomitantly adopting a differentiated morphology. Inhibition of PI3Ks reduced basal and LIF-stimulated phosphorylation of PKB/Akt, GSK3α/β, and S6 proteins. Importantly, LY294002 and Δp85 expression had no effect on LIF-induced phosphorylation of STAT3 at Tyr705, but did augment LIF-induced phosphorylation of ERKs in both short and long term incubations. Subsequently, we demonstrate that inhibition of MAP-Erk kinases (MEKs) reverses the effects of PI3K inhibition on Self-Renewal in a time- and dose-dependent manner, suggesting that the elevated ERK activity observed upon PI3K inhibition contributes to the functional response we observe. Surprisingly, upon long term inhibition of PI3Ks we observed a reduction in phosphorylation of β-catenin, the target of GSK-3 action in the canonical Wnt pathway, although no consistent alterations in cytosolic levels of β-catenin were observed, indicating this pathway is not playing a major role downstream of PI3Ks. Our studies support a role for PI3Ks in regulation of Self-Renewal and increase our understanding of the molecular signaling components involved in regulation of stem Cell fate.
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Regulation of Embryonic Stem Cell Self-Renewal by Phosphoinositide 3-Kinase-dependent Signaling
The Journal of biological chemistry, 2004Co-Authors: Nicholas R D Paling, Helen Wheadon, Heather K Bone, Melanie J WelhamAbstract:The maintenance of murine embryonic stem (ES) Cell Self-Renewal is regulated by leukemia inhibitory factor (LIF)-dependent activation of signal transducer and activator of transcription 3 (STAT3) and LIF-independent mechanisms including Nanog, BMP2/4, and Wnt signaling. Here we demonstrate a previously undescribed role for phosphoinositide 3-kinases (PI3Ks) in regulation of murine ES Cell Self-Renewal. Treatment with the reversible PI3K inhibitor, LY294002, or more specific inhibition of class I(A) PI3K via regulated expression of dominant negative Deltap85, led to a reduction in the ability of LIF to maintain Self-Renewal, with Cells concomitantly adopting a differentiated morphology. Inhibition of PI3Ks reduced basal and LIF-stimulated phosphorylation of PKB/Akt, GSK3alpha/beta, and S6 proteins. Importantly, LY294002 and Deltap85 expression had no effect on LIF-induced phosphorylation of STAT3 at Tyr(705), but did augment LIF-induced phosphorylation of ERKs in both short and long term incubations. Subsequently, we demonstrate that inhibition of MAP-Erk kinases (MEKs) reverses the effects of PI3K inhibition on Self-Renewal in a time- and dose-dependent manner, suggesting that the elevated ERK activity observed upon PI3K inhibition contributes to the functional response we observe. Surprisingly, upon long term inhibition of PI3Ks we observed a reduction in phosphorylation of beta-catenin, the target of GSK-3 action in the canonical Wnt pathway, although no consistent alterations in cytosolic levels of beta-catenin were observed, indicating this pathway is not playing a major role downstream of PI3Ks. Our studies support a role for PI3Ks in regulation of Self-Renewal and increase our understanding of the molecular signaling components involved in regulation of stem Cell fate.
Frederick J Livesey - One of the best experts on this subject based on the ideXlab platform.
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the level of the transcription factor pax6 is essential for controlling the balance between neural stem Cell self renewal and neurogenesis
PLOS Genetics, 2009Co-Authors: Stephen N Sansom, Dean S Griffiths, Andrea Faedo, Dirkjan Kleinjan, Youlin Ruan, James Smith, Veronica Van Heyningen, John L R Rubenstein, Frederick J LiveseyAbstract:Neural stem Cell Self-Renewal, neurogenesis, and Cell fate determination are processes that control the generation of specific classes of neurons at the correct place and time. The transcription factor Pax6 is essential for neural stem Cell proliferation, multipotency, and neurogenesis in many regions of the central nervous system, including the cerebral cortex. We used Pax6 as an entry point to define the Cellular networks controlling neural stem Cell Self-Renewal and neurogenesis in stem Cells of the developing mouse cerebral cortex. We identified the genomic binding locations of Pax6 in neocortical stem Cells during normal development and ascertained the functional significance of genes that we found to be regulated by Pax6, finding that Pax6 positively and directly regulates cohorts of genes that promote neural stem Cell Self-Renewal, basal progenitor Cell genesis, and neurogenesis. Notably, we defined a core network regulating neocortical stem Cell decision-making in which Pax6 interacts with three other regulators of neurogenesis, Neurog2, Ascl1, and Hes1. Analyses of the biological function of Pax6 in neural stem Cells through phenotypic analyses of Pax6 gain- and loss-of-function mutant cortices demonstrated that the Pax6-regulated networks operating in neural stem Cells are highly dosage sensitive. Increasing Pax6 levels drives the system towards neurogenesis and basal progenitor Cell genesis by increasing expression of a cohort of basal progenitor Cell determinants, including the key transcription factor Eomes/Tbr2, and thus towards neurogenesis at the expense of Self-Renewal. Removing Pax6 reduces cortical stem Cell Self-Renewal by decreasing expression of key Cell cycle regulators, resulting in excess early neurogenesis. We find that the relative levels of Pax6, Hes1, and Neurog2 are key determinants of a dynamic network that controls whether neural stem Cells self-renew, generate cortical neurons, or generate basal progenitor Cells, a mechanism that has marked parallels with the transcriptional control of embryonic stem Cell Self-Renewal.
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The Level of the Transcription Factor Pax6 Is Essential for Controlling the Balance between Neural Stem Cell Self-Renewal and Neurogenesis
PLoS genetics, 2009Co-Authors: Stephen N Sansom, Dean S Griffiths, Andrea Faedo, Dirkjan Kleinjan, Youlin Ruan, James Smith, John L R Rubenstein, Veronica Van Heyningen, Frederick J LiveseyAbstract:Neural stem Cell Self-Renewal, neurogenesis, and Cell fate determination are processes that control the generation of specific classes of neurons at the correct place and time. The transcription factor Pax6 is essential for neural stem Cell proliferation, multipotency, and neurogenesis in many regions of the central nervous system, including the cerebral cortex. We used Pax6 as an entry point to define the Cellular networks controlling neural stem Cell Self-Renewal and neurogenesis in stem Cells of the developing mouse cerebral cortex. We identified the genomic binding locations of Pax6 in neocortical stem Cells during normal development and ascertained the functional significance of genes that we found to be regulated by Pax6, finding that Pax6 positively and directly regulates cohorts of genes that promote neural stem Cell Self-Renewal, basal progenitor Cell genesis, and neurogenesis. Notably, we defined a core network regulating neocortical stem Cell decision-making in which Pax6 interacts with three other regulators of neurogenesis, Neurog2, Ascl1, and Hes1. Analyses of the biological function of Pax6 in neural stem Cells through phenotypic analyses of Pax6 gain- and loss-of-function mutant cortices demonstrated that the Pax6-regulated networks operating in neural stem Cells are highly dosage sensitive. Increasing Pax6 levels drives the system towards neurogenesis and basal progenitor Cell genesis by increasing expression of a cohort of basal progenitor Cell determinants, including the key transcription factor Eomes/Tbr2, and thus towards neurogenesis at the expense of Self-Renewal. Removing Pax6 reduces cortical stem Cell Self-Renewal by decreasing expression of key Cell cycle regulators, resulting in excess early neurogenesis. We find that the relative levels of Pax6, Hes1, and Neurog2 are key determinants of a dynamic network that controls whether neural stem Cells self-renew, generate cortical neurons, or generate basal progenitor Cells, a mechanism that has marked parallels with the transcriptional control of embryonic stem Cell Self-Renewal.