Eomesodermin, HAND1, and CSH1 proteins are induced by cellular stress in a stress‐activated protein kinase‐dependent manner

Awonuga, Awoniyi O.; Zhong, Wenjing; Abdallah, M.; Slater, Jill A.; Zhou, Shaoman; Xie, Yahong; Puscheck, Elizabeth E.; Rappolee, Daniel A.

doi:10.1002/mrd.21342

Cited by 29 publications

(58 citation statements)

References 51 publications

(108 reference statements)

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“…We used hyperosmotic sorbitol at 200 mM because this dose is not toxic to embryos, TSCs, or ESCs [41,55,56,65,79] but slows their proliferation and has significant effects in causing AMPK-dependent Cdx2 and Id2 loss [41,45], PL1 increase in TSCs [80], Oct4 and Rex1 loss and first lineage Dab2 and LRP2 markers in ESCs [65,81,82], and significant AMPK-dependent Id2 loss in blastocysts [41]. We had previously shown that 200 mM sorbitol causes Cdx2 and Id2 loss in two-cell embryos in an AMPK-dependent manner [45], and this report adds AMPK-dependent Rex1 and Oct4 loss to make up a group of four AMPK-regulated potency factors expressed in both ESC and TSC lineages by the blastocyst stage.…”

Section: Discussionmentioning

confidence: 99%

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Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos

Bolnick

Abdulhasan

Kilburn

et al. 2016

J Assist Reprod Genet

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Purpose The purpose of the present study is to test whether metformin, aspirin, or diet supplement (DS) BioResponse-3, 3′-Diindolylmethane (BR-DIM) can induce AMP-activated protein kinase (AMPK)-dependent potency loss in cultured embryos and whether metformin (Met) + Aspirin (Asa) or BR-DIM causes an AMPK-dependent decrease in embryonic development. Methods The methods used were as follows: culture post-thaw mouse zygotes to the two-cell embryo stage and test effects after 1-h AMPK agonists' (e.g., Met, Asa, BR-DIM, control hyperosmotic stress) exposure on AMPK-dependent loss of Oct4 and/or Rex1 nuclear potency factors, confirm AMPK dependence by reversing potency loss in two-cell-stage embryos with AMPK inhibitor compound C (CC), test whether Met + Asa (i.e., co-added) or DS BR-DIM decreases development of two-cell to blastocyst stage in an AMPK-dependent (CCsensitive) manner, and evaluate the level of Rex1 and Oct4 nuclear fluorescence in two-cell-stage embryos and rate of two-cell-stage embryo development to blastocysts. Result(s) Met, Asa, BR-DIM, or hyperosmotic sorbitol stress induces rapid~50-85 % Rex1 and/or Oct4 protein loss in twocell embryos. This loss is~60-90 % reversible by co-culture with AMPK inhibitor CC. Embryo development from twocell to blastocyst stage is decreased in culture with either Met + Asa or BR-DIM, and this is either >90 or~60 % reversible with CC, respectively. Conclusion These experimental designs here showed that Met-, Asa-, BR-DIM-, or sorbitol stress-induced rapid potency loss in two-cell embryos is AMPK dependent as suggested by inhibition of Rex1 and/or Oct4 protein loss with an AMPK inhibitor. The DS BR-DIM or fertility drugs (e.g., Met + Asa)Capsule Drugs metformin and aspirin and diet supplement BR-DIM cause AMPK-dependent potency loss and decrease embryonic development from two-cell to blastocyst stage. Reprod Genet (2016) 33:1027-1039 DOI 10.1007 that are used to enhance maternal metabolism to support fertility can also chronically slow embryo growth and block development in an AMPK-dependent manner.

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Section: Discussionmentioning

confidence: 99%

“…For TSCs, it is clear that dominant negative Id2 loss is needed to enable stem cell differentiation to produce antiluteolytic placental lactogen (PL)1 in rodents [41,80]. In the two-cell-stage embryo, the role of Oct4 and other potency factors is not established.…”

Section: Discussionmentioning

confidence: 99%

Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos

Bolnick

Abdulhasan

Kilburn

et al. 2016

J Assist Reprod Genet

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“…In this investigation, the expression of Id isoforms in the SM10 labyrinthine progenitor cell line and the effect of Id2 overexpression and knockdown on TGF-b-induced differentiation were examined. The expression of Id proteins is essential for normal development and differentiation of several cell types [28,51,[75][76][77][78][79][80]. Id isoforms are also expressed in the placenta, and this suggests their importance in directing trophoblast self-renewal and differentiation [15,[29][30][31][32]43,76].…”

Section: Discussionmentioning

confidence: 99%

Id2 Mediates Differentiation of Labyrinthine Placental Progenitor Cell Line, SM10

Selesniemi

Albers

Brown

2016

Stem Cells and Development

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The placenta is an organ that is formed transiently during pregnancy, and appropriate placental development is necessary for fetal survival and growth. Proper differentiation of the labyrinthine layer of the placenta is especially crucial, as it establishes the fetal-maternal interface that is involved in physiological exchange processes. Although previous studies have indicated the importance of inhibitor of differentiation/inhibitor of DNA binding-2 (Id2) helix-loop-helix transcriptional regulator in mediating cell differentiation, the ability of Id2 to regulate differentiation toward the labyrinthine (transport) lineage of the placenta has yet to be determined. In the current study, we have generated labyrinthine trophoblast progenitor cells with increased (SM10-Id2) or decreased (SM10-Id2-shRNA) Id2 expression and determined the effect on TGF-b-induced differentiation. Our Id2 overexpression and knockdown analyses indicate that Id2 mediates TGF-b-induced morphological differentiation of labyrinthine trophoblast cells, as Id2 overexpression prevents differentiation and Id2 knockdown results in differentiation. Thus, our data indicate that Id2 is an important molecular mediator of labyrinthine trophoblast differentiation. An understanding of the regulators of trophoblast progenitor differentiation toward the labyrinthine lineage may offer insights into events governing pregnancy-associated disorders, such as placental insufficiency, fetal growth restriction, and preeclampsia.

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“…Interestingly, JNK prioritizes differentiation of TSCs stressed by hyperosmotic sorbitol, benzopyrene, or hypoxic O 2 below 2%, by inducing first lineage [5,7,64] and suppressing later lineages [5]. JNK appears to mediate stress-induced endoderm, the first lineage arising from ESCs, but it remains to be determined whether JNK suppresses later lineages.…”

Section: Discussionmentioning

confidence: 99%

“…TGCs maintain early pregnancy by producing the hormones that stimulate uterine changes necessary to support an embryo. When placental trophoblast stem cells (TSCs), precursors to TGCs, were confronted with hyperosmotic stress in vitro, the stress enzymes that were activated modulated lineage TF expression [2,[5][6][7]. Nearly all surviving TSCs terminally differentiated to first-lineage TGCs [5,7,8] and later lineages were suppressed [5,8].…”

Section: Introductionmentioning

confidence: 99%

Stress-Induced Enzyme Activation Primes Murine Embryonic Stem Cells to Differentiate Toward the First Extraembryonic Lineage

Slater

Zhou

Puscheck

et al. 2014

Stem Cells and Development

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Extracellular stresses influence transcription factor (TF) expression and therefore lineage identity in the periimplantation mouse embryo and its stem cells. This potentially affects pregnancy outcome. To understand the effects of stress signaling during this critical period of pregnancy, we exposed cultured murine embryonic stem cells (mESCs) to hyperosmotic stress. We then measured stress-enzyme-dependent regulation of key pluripotency and lineage TFs. Hyperosmotic stress slowed mESC accumulation due to slowing of the cell cycle over 72 h, after a small apoptotic response within 12 h. Phosphoinositide 3-kinase (PI3K) enzymatic signaling was responsible for stem cell survival under stressed conditions. Stress initially triggered mESC differentiation after 4 h through MEK1, c-Jun N-terminal kinase ( JNK), and PI3K enzymatic signaling, which led to proteasomal degradation of Oct4, Nanog, Sox2, and Rex1 TF proteins. Concurrent with this post-transcriptional effect was the decreased accumulation of potency TF mRNA transcripts. After 12-24 h of stress, cells adapted, cell cycle resumed, and Oct4 and Nanog mRNA and protein expression returned to approximately normal levels. The TF protein recovery was mediated by p38MAPK and PI3K signaling, as well as by MEK2 and/or MEK1. However, due to JNK signaling, Rex1 expression did not recover. Probing for downstream lineages revealed that although mESCs did not differentiate morphologically during 24 h of stress, they were primed to differentiate by upregulating markers of the first lineage differentiating from mESCs, extraembryonic endoderm. Thus, although two to three TFs that mark pluripotency recover expression by 24 h of stress, there is nonetheless sustained Rex1 suppression and a priming of mESCs for differentiation to the earliest lineage.

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Eomesodermin, HAND1, and CSH1 proteins are induced by cellular stress in a stress‐activated protein kinase‐dependent manner

Cited by 29 publications

References 51 publications

Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos

Commonly used fertility drugs, a diet supplement, and stress force AMPK-dependent block of stemness and development in cultured mammalian embryos

Id2 Mediates Differentiation of Labyrinthine Placental Progenitor Cell Line, SM10

Stress-Induced Enzyme Activation Primes Murine Embryonic Stem Cells to Differentiate Toward the First Extraembryonic Lineage

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