Retinoic Acid Induces Embryonic Stem Cells (ESCs) Transition to 2 Cell-Like State Through a Coordinated Expression of Dux and Duxbl1

Tagliaferri, Daniela; Mazzone, P.; Noviello, Teresa Maria Rosaria; Addeo, Martina; Angrisano, Tiziana; Vecchio, Luigi Del; Visconte, Feliciano; Ruggieri, Vitalba; Russi, Sabino; Caivano, Antonella; Cantone, Irene; Felice, Mario De; Ceccarelli, Michele; Cerulo, Luigi; Falco, Geppino

doi:10.3389/fcell.2019.00385

Cited by 25 publications

(30 citation statements)

References 47 publications

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“…Our data identify the RA signaling pathway as a core component of 2CLC identity and key regulator of 2CLC emergence. Previous work has shown that RA can increase the number of Zscan4 + cells in ES cell cultures 15 , 43 , which constitute around 5% of the ES cell population and are an intermediate cellular state between ES and 2CLCs 10 . In contrast to 2CLCs, RAR activity is not necessary for the emergence of the ZSCAN4 + population, although their numbers decrease when treated with a RAR inhibitor 15 .…”

Section: Discussionmentioning

confidence: 98%

“…Previous work has shown that RA can increase the number of Zscan4 + cells in ES cell cultures 15 , 43 , which constitute around 5% of the ES cell population and are an intermediate cellular state between ES and 2CLCs 10 . In contrast to 2CLCs, RAR activity is not necessary for the emergence of the ZSCAN4 + population, although their numbers decrease when treated with a RAR inhibitor 15 . Together with previous work, our data support a model whereby RA induces both the ZSCAN4 + cells 43 as well as the transition from the ZSCAN4 + state towards the 2CLC state.…”

Section: Discussionmentioning

confidence: 98%

“…Upon exit from pluripotency, 2CLCs arise from an intermediate cellular population characterized by the expression of ZSCAN4. The number of ZSCAN4 + cells fluctuates in cell cultures, and can increase following changes in metabolites in the medium or the addition of signaling molecules such as retinoic acid (RA) 14 , 15 . Much effort has been made towards understanding the mechanisms regulating the transcriptional program in 2CLCs and in 2-cell stage embryos 8 – 10 , 16 – 21 .…”

Section: Mainmentioning

confidence: 99%

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Retinoic acid signaling is critical during the totipotency window in early mammalian development

Iturbide

Segura

Noll

et al. 2021

Nat Struct Mol Biol

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Totipotent cells hold enormous potential for regenerative medicine. Thus, the development of cellular models recapitulating totipotent-like features is of paramount importance. Cells resembling the totipotent cells of early embryos arise spontaneously in mouse embryonic stem (ES) cell cultures. Such ‘2-cell-like-cells’ (2CLCs) recapitulate 2-cell-stage features and display expanded cell potential. Here, we used 2CLCs to perform a small-molecule screen to identify new pathways regulating the 2-cell-stage program. We identified retinoids as robust inducers of 2CLCs and the retinoic acid (RA)-signaling pathway as a key component of the regulatory circuitry of totipotent cells in embryos. Using single-cell RNA-seq, we reveal the transcriptional dynamics of 2CLC reprogramming and show that ES cells undergo distinct cellular trajectories in response to RA. Importantly, endogenous RA activity in early embryos is essential for zygotic genome activation and developmental progression. Overall, our data shed light on the gene regulatory networks controlling cellular plasticity and the totipotency program.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Section: Mainmentioning

confidence: 99%

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Retinoic acid signaling is critical during the totipotency window in early mammalian development

Iturbide

Segura

Noll

et al. 2021

Nat Struct Mol Biol

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“…In order to investigate if TR antagonist 1-850 treatment may have an effect in the expression of TR-regulated genes, we studied the expression of Krüppel-like factor 9 (Klf9) mRNA, which is a TR-regulated gene [ 23 , 24 ]. We observed a significant increase of klf9 mRNA in the RA treated group of cells (Student’s t test, p = 0.0111), however no significant effect was observed in the group of cells treated with TR-antagonist 1-850 ( Supplemental Figure ).…”

Section: Resultsmentioning

confidence: 99%

Thyroid Hormone Signaling in Embryonic Stem Cells: Crosstalk with the Retinoic Acid Pathway

Fernández

Pannella

Baldassarro

et al. 2020

IJMS

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While the role of thyroid hormones (THs) during fetal and postnatal life is well-established, their role at preimplantation and during blastocyst development remains unclear. In this study, we used an embryonic stem cell line isolated from rat (RESC) to study the effects of THs and retinoic acid (RA) on early embryonic development during the pre-implantation stage. The results showed that THs play an important role in the differentiation/maturation processes of cells obtained from embryoid bodies (EB), with thyroid hormone nuclear receptors (TR) (TRα and TRβ), metabolic enzymes (deiodinases 1, 2, 3) and membrane transporters (Monocarboxylate transporters -MCT- 8 and 10) being expressed throughout in vitro differentiation until the Embryoid body (EB) stage. Moreover, thyroid hormone receptor antagonist TR (1-850) impaired RA-induced neuroectodermal lineage specification. This effect was significantly higher when cells were treated with retinoic acid (RA) to induce neuroectodermal lineage, studied through the gene and protein expression of nestin, an undifferentiated progenitor marker from the neuroectoderm lineage, as established by nestin mRNA and protein regulation. These results demonstrate the contribution of the two nuclear receptors, TR and RA, to the process of neuroectoderm maturation of the in vitro model embryonic stem cells obtained from rat.

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“…It has been shown that nuclear factor-1 (NF1), recruited by the RA-RXR/RAR complex, could stabilize the status of the open nucleosome structure of RAresponsive genes, leading to cell lineage-specific epigenetic modifications and transcription activation (2). Another study has demonstrated that RA can initiate embryonic stem cells to two-cell-like (a rare population of cells resembling twocell stage embryos in pluripotent embryonic stem cell cultures that display molecular features of totipotency and broader developmental plasticity) reprogramming through a coordinated expression of double homeobox (Dux) and Dux B-like 1 (Duxbl1) in a RARE-dependent manner (13). Besides, RAR/RXRs can interact with other nuclear proteins to change the transcription status of genes, for example, RA administration to stem cells caused the rapid disassociation of polycomb group proteins from RA primary target genes (Hoxa1, Cyp26a1, RARb2, etc.)…”

Section: General Effects Of Ra On Immunomodulation Differentiation Of Stem Cells and Anticancer Therapymentioning

confidence: 99%

Disparate roles of retinoid acid signaling molecules in kidney disease

Chen

Liu

et al. 2021

American Journal of Physiology-Renal Physiology

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RA (Retinoid acid) is synthesized mainly in the liver and has multiple functions in development, cell differentiation and proliferation, and regulation of inflammation. RA has been used to treat multiple diseases such as cancer and skin disorders. The kidney is a major organ for RA metabolism, which is altered in the diseased condition. RA is known to have renal protective effects in multiple animal models of kidney disease. RA has been shown to ameliorate podocyte injury through induction of expression of differentiation markers and regeneration of podocytes from its progenitor cells in animal models of kidney disease. The effects of RA in podocytes are mediated mainly by activation of cAMP/PKA pathway via retinoic acid receptor-α (RARα) and activation of its downstream transcription factor KLF15. Screening of RA signaling molecules in human kidney disease reveals RARRES1 as a risk gene for glomerular disease progression. RARRES1, a podocyte-specific growth arrest gene, is regulated by both high doses of RA and TNFα. Mechanistically, RARRES1 is cleaved by MMPs to generate soluble RARRES1 which then induces podocyte apoptosis through interaction with intracellular RIOK1. Therefore, a high dose of RA may induce podocyte toxicity through the upregulation of RARRES1. Based on the current findings, to avoid potential side effects we propose three strategies to develop future therapies of RA for glomerular disease: 1) develop RARα- and KLF15-specific agonists; 2) use the combination of a low dose of RARα agonist with PDE4 inhibitors; and 3) use the combination of RARα agonist with RARRES1 inhibitors.

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Retinoic Acid Induces Embryonic Stem Cells (ESCs) Transition to 2 Cell-Like State Through a Coordinated Expression of Dux and Duxbl1

Cited by 25 publications

References 47 publications

Retinoic acid signaling is critical during the totipotency window in early mammalian development

Retinoic acid signaling is critical during the totipotency window in early mammalian development

Thyroid Hormone Signaling in Embryonic Stem Cells: Crosstalk with the Retinoic Acid Pathway

Disparate roles of retinoid acid signaling molecules in kidney disease

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