Inhibition of mTOR induces a paused pluripotent state

Bulut-Karslıoğlu, Aydan; Biechele, Steffen; Hu, Jin; Macrae, Trisha A.; Hejna, Miroslav; Gertsenstein, Marina; Song, Jun S.; Ramalho-Santos, Miguel

doi:10.1038/nature20578

Cited by 206 publications

(338 citation statements)

References 38 publications

(50 reference statements)

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Section: Discussionsupporting

confidence: 68%

“…It is therefore interesting to investigate whether Fgf8a's effect on MGPC proliferation requires mTOR. A similar effect of mTOR inhibition on pluripotency was observed in mouse blastocyst and ESCs (Bulut‐Karslioglu et al, ). Together with our results, it suggests that the paused multipotent or pluripotent state induced by mTOR inhibition may apply not only to ESCs but also to adult stem and progenitor cells.…”

Section: Discussionsupporting

confidence: 63%

“…This kinase is a central component of the mTOR signaling pathway and forms multiprotein complexes, mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) (Meng, Frank, & Jewell, 2018). During mammalian development, mTOR activity is required for embryonic stem cell (ESC) self-renew and differentiation (Bulut-Karslioglu et al, 2016;Cherepkova, Sineva, & Pospelov, 2016;Gomez-Salinero et al, 2016). In the nervous system, mTOR is necessary for the maintenance, proliferation, and differentiation of neural stem cell and neural progenitor cell (Lee, Lim, Park, Park, & Koh, 2016;Li et al, 2017;Romine, Gao, Xu, So, & Chen, 2015;Yang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

Zhang

Hou

et al. 2019

Glia

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Upon retina injury, Müller glia in the zebrafish retina respond by generating multipotent progenitors to repair the retina. However, the complete mechanisms underlying retina regeneration remain elusive. Here we report inflammation‐induced mammalian target of rapamycin (mTOR) signaling in the Müller glia is essential for retina regeneration in adult zebrafish. We show after a stab injury, mTOR is rapidly activated in Müller glia and later Müller glia‐derived progenitor cells (MGPCs). Importantly, mTOR is required for Müller glia dedifferentiation, as well as the proliferation of Müller glia and MGPCs. Interestingly, transient mTOR inhibition by rapamycin only reversibly suppresses MGPC proliferation, while its longer suppression by knocking down Raptor significantly inhibits the regeneration of retinal neurons. We further show mTOR promotes retina regeneration by regulating the mRNA expression of key reprogramming factors ascl1a and lin‐28a, cell cycle‐related genes and critical cytokines. Surprisingly, we identify microglia/macrophage‐mediated inflammation as an important upstream regulator of mTOR in the Müller glia and it promotes retina regeneration through mTOR. Our study not only demonstrates the important functions of mTOR but also reveals an interesting link between inflammation and the mTOR signaling during retina regeneration.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

Zhang

Hou

et al. 2019

Glia

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“…The cessation of hypertranscription is likely to be initiated by changes in intercellular signaling pathways. In support of this notion, we recently found that inhibition of mTor, a major nutrient sensor and promoter of growth (Zoncu et al, 2011), induces a state of global hypo transcription and developmental pausing in blastocysts and ES cells (Bulut-Karslioglu et al, 2016). Moreover, it is possible that there are instances of post-mitotic hypertranscription, including in cases of large-scale metabolic shifts, cellular hypertrophy or high levels of protein secretion.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 87%

Hypertranscription in Development, Stem Cells, and Regeneration

2017

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SUMMARY Cells can globally up-regulate their transcriptome during specific transitions, a phenomenon called hypertranscription. Evidence for hypertranscription dates back over 70 years, but it has gone largely ignored in the genomics era until recently. We discuss data supporting the notion that hypertranscription is a unifying theme in embryonic development, stem cell biology, regeneration and cell competition. We review the history, methods for analysis, underlying mechanisms and biological significance of hypertranscription.

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“…Several studies have demonstrated that mTOR is essential for the maintenance of pluripotency and the repression of differentiation genes in ESCs grown under standard conditions . In addition, a more recent study found that partial inhibition of mTOR in mESCs induces the cells to adopt a “paused” state resembling embryonic diapause . The mechanism of this effect is not fully understood, but the authors speculate that the paused state is induced by the combined effects of mTOR inhibition on transcription, translation, and metabolism.…”

Section: Metabolismmentioning

confidence: 99%

Cell fate decisions: emerging roles for metabolic signals and cell morphology

et al. 2017

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Understanding how cell fate decisions are regulated is a fundamental goal of developmental and stem cell biology. Most studies on the control of cell fate decisions address the contributions of changes in transcriptional programming, epigenetic modifications, and biochemical differentiation cues. However, recent studies have found that other aspects of cell biology also make important contributions to regulating cell fate decisions. These cues can have a permissive or instructive role and are integrated into the larger network of signaling, functioning both upstream and downstream of developmental signaling pathways. Here, we summarize recent insights into how cell fate decisions are influenced by four aspects of cell biology: metabolism, reactive oxygen species (ROS), intracellular pH (pHi), and cell morphology. For each topic, we discuss how these cell biological cues interact with each other and with protein-based mechanisms for changing gene transcription. In addition, we highlight several questions that remain unanswered in these exciting and relatively new areas of the field.

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Inhibition of mTOR induces a paused pluripotent state

Cited by 206 publications

References 38 publications

Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

Inflammation‐induced mammalian target of rapamycin signaling is essential for retina regeneration

Hypertranscription in Development, Stem Cells, and Regeneration

Cell fate decisions: emerging roles for metabolic signals and cell morphology

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