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Esrrb Is a Pivotal Target of the Gsk3/Tcf3 Axis Regulating Embryonic Stem Cell Self-Renewal

Inhibition of glycogen synthase kinase-3 (Gsk3) supports mouse embryonic stem cells (ESCs) by modulating Tcf3, but the critical targets downstream of Tcf3 are unclear. We analyzed the intersection between genome localization and transcriptome data sets to identify genes repressed by Tcf3. Among thes...

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Autores principales: Martello, Graziano, Sugimoto, Toshimi, Diamanti, Evangelia, Joshi, Anagha, Hannah, Rebecca, Ohtsuka, Satoshi, Göttgens, Berthold, Niwa, Hitoshi, Smith, Austin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465555/
https://www.ncbi.nlm.nih.gov/pubmed/23040478
http://dx.doi.org/10.1016/j.stem.2012.06.008
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author Martello, Graziano
Sugimoto, Toshimi
Diamanti, Evangelia
Joshi, Anagha
Hannah, Rebecca
Ohtsuka, Satoshi
Göttgens, Berthold
Niwa, Hitoshi
Smith, Austin
author_facet Martello, Graziano
Sugimoto, Toshimi
Diamanti, Evangelia
Joshi, Anagha
Hannah, Rebecca
Ohtsuka, Satoshi
Göttgens, Berthold
Niwa, Hitoshi
Smith, Austin
author_sort Martello, Graziano
collection PubMed
description Inhibition of glycogen synthase kinase-3 (Gsk3) supports mouse embryonic stem cells (ESCs) by modulating Tcf3, but the critical targets downstream of Tcf3 are unclear. We analyzed the intersection between genome localization and transcriptome data sets to identify genes repressed by Tcf3. Among these, manipulations of Esrrb gave distinctive phenotypes in functional assays. Knockdown and knockout eliminated response to Gsk3 inhibition, causing extinction of pluripotency markers and loss of colony forming capability. Conversely, forced expression phenocopied Gsk3 inhibition or Tcf3 deletion by suppressing differentiation and sustaining self-renewal. Thus the nuclear receptor Esrrb is necessary and sufficient to mediate self-renewal downstream of Gsk3 inhibition. Leukaemia inhibitory factor (LIF) regulates ESCs through Stat3, independently of Gsk3 inhibition. Consistent with parallel operation, ESCs in LIF accommodated Esrrb deletion and remained pluripotent. These findings highlight a key role for Esrrb in regulating the naive pluripotent state and illustrate compensation among the core pluripotency factors.
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spelling pubmed-34655552012-11-06 Esrrb Is a Pivotal Target of the Gsk3/Tcf3 Axis Regulating Embryonic Stem Cell Self-Renewal Martello, Graziano Sugimoto, Toshimi Diamanti, Evangelia Joshi, Anagha Hannah, Rebecca Ohtsuka, Satoshi Göttgens, Berthold Niwa, Hitoshi Smith, Austin Cell Stem Cell Article Inhibition of glycogen synthase kinase-3 (Gsk3) supports mouse embryonic stem cells (ESCs) by modulating Tcf3, but the critical targets downstream of Tcf3 are unclear. We analyzed the intersection between genome localization and transcriptome data sets to identify genes repressed by Tcf3. Among these, manipulations of Esrrb gave distinctive phenotypes in functional assays. Knockdown and knockout eliminated response to Gsk3 inhibition, causing extinction of pluripotency markers and loss of colony forming capability. Conversely, forced expression phenocopied Gsk3 inhibition or Tcf3 deletion by suppressing differentiation and sustaining self-renewal. Thus the nuclear receptor Esrrb is necessary and sufficient to mediate self-renewal downstream of Gsk3 inhibition. Leukaemia inhibitory factor (LIF) regulates ESCs through Stat3, independently of Gsk3 inhibition. Consistent with parallel operation, ESCs in LIF accommodated Esrrb deletion and remained pluripotent. These findings highlight a key role for Esrrb in regulating the naive pluripotent state and illustrate compensation among the core pluripotency factors. Cell Press 2012-10-05 /pmc/articles/PMC3465555/ /pubmed/23040478 http://dx.doi.org/10.1016/j.stem.2012.06.008 Text en © 2012 ELL & Excerpta Medica. https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license
spellingShingle Article
Martello, Graziano
Sugimoto, Toshimi
Diamanti, Evangelia
Joshi, Anagha
Hannah, Rebecca
Ohtsuka, Satoshi
Göttgens, Berthold
Niwa, Hitoshi
Smith, Austin
Esrrb Is a Pivotal Target of the Gsk3/Tcf3 Axis Regulating Embryonic Stem Cell Self-Renewal
title Esrrb Is a Pivotal Target of the Gsk3/Tcf3 Axis Regulating Embryonic Stem Cell Self-Renewal
title_full Esrrb Is a Pivotal Target of the Gsk3/Tcf3 Axis Regulating Embryonic Stem Cell Self-Renewal
title_fullStr Esrrb Is a Pivotal Target of the Gsk3/Tcf3 Axis Regulating Embryonic Stem Cell Self-Renewal
title_full_unstemmed Esrrb Is a Pivotal Target of the Gsk3/Tcf3 Axis Regulating Embryonic Stem Cell Self-Renewal
title_short Esrrb Is a Pivotal Target of the Gsk3/Tcf3 Axis Regulating Embryonic Stem Cell Self-Renewal
title_sort esrrb is a pivotal target of the gsk3/tcf3 axis regulating embryonic stem cell self-renewal
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465555/
https://www.ncbi.nlm.nih.gov/pubmed/23040478
http://dx.doi.org/10.1016/j.stem.2012.06.008
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