Esrrb Complementation Rescues Development of Nanog-Null Germ Cells

Zhang, Man; Leitch, Harry G.; Tang, Walfred W.C.; Festuccia, Nicola; Hall-Ponsele, Elisa; Nichols, Jennifer; Surani, M. Azim; Smith, Austin; Chambers, Ian

doi:10.1016/j.celrep.2017.12.060

Cited by 47 publications

(60 citation statements)

References 35 publications

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“…Among these, Esrrb is the most strongly upregulated TF. Consistent with this, ESRRB is able to mediate several downstream effects of NANOG, both in pluripotent cells and primordial germ cells (Festuccia et al , 2012; Zhang et al , 2018). NANOG protein is expressed in the nuclei of ESCs cultured in LIF/FCS in a heterogeneous manner, a feature shared with several other pluripotency proteins, including ESRRB (Chambers et al , 2007; Torres‐Padilla & Chambers, 2014).…”

Section: Discussionmentioning

confidence: 71%

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

et al. 2018

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Self‐renewal of embryonic stem cells (ESCs) cultured in LIF/fetal calf serum (FCS) is incomplete with some cells initiating differentiation. While this is reflected in heterogeneous expression of naive pluripotency transcription factors (TFs), the link between TF heterogeneity and differentiation is not fully understood. Here, we purify ESCs with distinct TF expression levels from LIF/FCS cultures to uncover early events during commitment from naïve pluripotency. ESCs carrying fluorescent Nanog and Esrrb reporters show Esrrb downregulation only in Nanoglow cells. Independent Esrrb reporter lines demonstrate that Esrrbnegative ESCs cannot effectively self‐renew. Upon Esrrb loss, pre‐implantation pluripotency gene expression collapses. ChIP‐Seq identifies different regulatory element classes that bind both OCT4 and NANOG in Esrrbpositive cells. Class I elements lose NANOG and OCT4 binding in Esrrbnegative ESCs and associate with genes expressed preferentially in naïve ESCs. In contrast, Class II elements retain OCT4 but not NANOG binding in ESRRB‐negative cells and associate with more broadly expressed genes. Therefore, mechanistic differences in TF function act cumulatively to restrict potency during exit from naïve pluripotency.

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Section: Discussionmentioning

confidence: 71%

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

et al. 2018

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“…Indeed, Nanog ‐null mouse embryonic stem cells (mESCs) could still form PGCs at E11.5 in chimeric embryos, but exhibited reduced viability thereafter (Chambers et al, ). Notably, this compromised development of Nanog ‐null PGCs could be rescued by introducing exogenous Esrrb (Zhang et al, ), a key downstream target of Nanog (Festuccia et al, ), providing evidence for a Nanog ‐ Esrrb hierarchy in mPGC development and highlighting functional conservation of the naïve pluripotency network in both ESCs and PGCs (Figure b). Intriguingly, while Nanog is not strictly essential for germline development in vivo , its forced induction can enhance the formation of PGC‐like cells (PGCLCs) in vitro , as detailed below (Murakami et al, ).…”

Section: The Mouse Paradigm For Inducing Embryonic Pgcsmentioning

confidence: 99%

Committing the primordial germ cell: An updated molecular perspective

Tan

Tee

2018

WIREs Mechanisms of Disease

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The germ line is a crucial cell lineage that is distinct from somatic cells, and solely responsible for the trans-generational transmission of hereditary information in metazoan sexual reproduction. Primordial germ cells (PGCs)-the precursors to functional germ cells-are among the first cell types to be allocated in embryonic development, and this lineage commitment is a critical event in partitioning germ line and somatic tissues. Classically, mammalian PGC development has been largely informed by investigations on mouse embryos and embryonic stem cells. Recent findings from corresponding nonrodent systems, however, have indicated that murine PGC specification may not be fully archetypal. In this review, we outline the current understanding of molecular mechanisms in PGC specification, emphasizing key transcriptional events, and focus on salient differences between early human and mouse PGC commitment. Beyond these latest findings, we also contemplate the future outlook of inquiries in this field, highlighting the importance of comprehensively understanding early fate decisions that underlie the segregation of this unique lineage. This article is categorized under: Developmental Biology > Stem Cell Biology and Regeneration Biological Mechanisms > Cell Fates Physiology > Mammalian Physiology in Health and Disease.

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“…Oct4 (official gene symbol Pou5f1) is continuously expressed up to embryonic day (E) 8.5, initially throughout the epiblast and subsequently showing progressive restriction to the posterior part of the embryo (4,5). Nanog is re-expressed at E5.5 but only in the posterior-proximal region where it has been shown to control development of the primordial germ cells (6,7), and is turned off by E7.5 (8). Loss-of-function approaches to investigating the role of Oct4 and Nanog at these stages have proved difficult because preimplantation lethality precludes analysis of later phenotypes (9,10).…”

Section: Introductionmentioning

confidence: 99%

Pluripotency factors regulate the onset of Hox cluster activation in the early embryo

López‐Jiménez

Aja

Badía-Careaga

et al. 2019

Preprint

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Pluripotent cells are a transient population present in the early mammalian embryo dependent on transcription factors, such as OCT4 and NANOG, which maintain pluripotency while simultaneously suppressing lineage specification. Interestingly, these factors are not exclusive to uncommitted cells, but are also expressed during early phases of differentiation. However, their role in the transition from pluripotency to lineage specification is largely unknown. Using genetic models for controlled Oct4 or Nanog expression during postimplantation stages, we found that pluripotency factors play a dual role in regulating key lineage specifiers, initially repressing their expression and later being required for their proper activation. We show that the HoxB cluster is coordinately regulated in this way by OCT4 binding sites located at the 3' end of the cluster. Our results show that core pluripotency factors are not limited to maintaining the pre-committed epiblast, but are also necessary for the proper deployment of subsequent developmental programs. Dual regulation of Hox genes by pluripotency factors Lopez-Jimenez et al. 3

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Esrrb Complementation Rescues Development of Nanog-Null Germ Cells

Cited by 47 publications

References 35 publications

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

Esrrb extinction triggers dismantling of naïve pluripotency and marks commitment to differentiation

Committing the primordial germ cell: An updated molecular perspective

Pluripotency factors regulate the onset of Hox cluster activation in the early embryo

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