NOSTRIN: A novel modulator of trophoblast giant cell differentiation

Chakraborty, Shreeta; Ain, Rupasri

doi:10.1016/j.scr.2018.07.023

Cited by 20 publications

(26 citation statements)

References 43 publications

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“…At 90–95% cell confluence, MEFs were treated with mitomycin C (Sigma-Aldrich) for 3 h and washed with PBS. Cells were then fed with TS complete medium and cultured for 72 h. The conditioned medium was collected in three batches after every 72 h. The conditioned medium was centrifuged and filtered to remove cell debris and stored at −80°C and used for culturing TS cells ( Chakraborty & Ain, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

MicroRNA regulation of murine trophoblast stem cell self-renewal and differentiation

Saha

Ain

2020

Life Sci. Alliance

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Proper placentation is fundamental to successful pregnancy. Placenta arises from differentiation of trophoblast stem (TS) cells during development. Despite being recognized as the counterpart of ES cells in placental development, the role of regulatory miRNAs in TS cell differentiation remains inadequately explored. Here, we have identified complete repertoire of microRNAs present in mouse trophoblast cells in proliferative and differentiated state. We demonstrated that two miRNA clusters, -290 and -322, displayed reciprocal expression during trophoblast differentiation. Loss of miR-290 cluster members or gain in miR-322 cluster members led to differentiation of TS cells. The trophoblast stemness factor, CDX2, transactivated the miR-290 cluster and Cyclin D1. MiR-290 cluster members repressed cell cycle repressors, P21, P27, WEE1, RBL2, and E2F7, in TS cells. MiR-322 cluster members repressed the cell cycle activators, CYCLIN D1, CYCLIN E1, CDC25B, and CDX2, to induce differentiation. Taken together, our findings highlight the importance of posttranscriptional regulation by conserved miRNA clusters that form a regulatory network with CDX2, cell cycle activators, and repressors in equipoising TS cell self-renewal and differentiation.

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Section: Methodsmentioning

confidence: 99%

MicroRNA regulation of murine trophoblast stem cell self-renewal and differentiation

Saha

Ain

2020

Life Sci. Alliance

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“…Western blotting was performed as described previously 26,27 . Total protein was isolated from TSCs and differentiated trophoblast cells by mild trypsinization and scraping respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Western blotting was performed as described previously. 26,27 Total Figure 1C). Similarly, Amot transcript levels gradually increased in the placenta from E12.5 to E14.5 and subsequently to E17.5 (P < .005) ( Figure 1D).…”

Section: Western Blot and Immunoprecipitationmentioning

confidence: 99%

“…To study the trophoblast specific role of AMOT, the well-known ex vivo model of murine TSCs 23 Withdrawal of these mitogenic stimuli led to their differentiation into major trophoblast cell types. 24,27,28 Differentiated trophoblast cells were maintained in culture for 6 days which ensured differentiation toward the default TGC trajectory. The purity of TSCs and differentiated trophoblast cells were assessed by quantitative analysis of lineage specific marker Cdx2 (for TSCs) and Prl2c2 (for TGCs) ( Figure S2A…”

Section: Angiomotin Expression Increases In Tscs Upon Induction Of mentioning

confidence: 99%

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Sequestration of eIF4A by angiomotin: A novel mechanism to restrict global protein synthesis in trophoblast cells

et al. 2020

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Enrichment of angiomotin (AMOT) in the ectoplacental cone of E7.5 murine placenta prompted our investigation on the role of AMOT in trophoblast differentiation. We show here that AMOT levels increased in mouse placenta during gestation and also upon induction of differentiation in trophoblast stem cell ex vivo. Proteomic data unravelling AMOT-interactome in trophoblast cells indicated a majority of AMOT interactors to be involved in protein translation. In-depth analysis of AMOT-interactome led to identification of eukaryotic translation initiation factor 4A (eIF4A) as the most plausible AMOT interactor. Loss of function of AMOT enhanced, whereas, gain in function resulted in decline of global protein synthesis in trophoblast cells. Bioinformatics analysis evaluating the potential energy of AMOT-eIF4A binding suggested a strong AMOT-eIF4A interaction using a distinct groove encompassing amino acid residue positions 238 to 255 of AMOT. Co-immunoprecipitation of AMOT with eIF4A reaffirmed AMOT-eIF4A association in trophoblast cells. Deletion of 238 to 255 amino acids of AMOT resulted in abrogation of AMOT-eIF4A interaction. In addition, 238 to 255 amino acid deletion of AMOT was ineffective in eliciting AMOT's function in reducing global protein synthesis. Interestingly, AMOT-dependent sequestration of eIF4A dampened its loading to the m7-GTP cap and hindered its interaction with eIF4G. Furthermore, enhanced AMOT expression in placenta was associated with intrauterine growth restriction in both rats and humans. These results not only highlight a hitherto unknown novel function of AMOT in trophoblast cells but also have broad biological implications as AMOT might be an inbuilt switch to check protein synthesis in developmentally indispensable trophoblast cells.

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“…Table S5. Primers used for experimental validation of differentially expressed genes, differentially expressed exons and novel identified exons [7,15,16,33,[85][86][87][88][89][90][91][92][93]. Authors' contributions AF, AM, and MT conceived and designed the study with RU providing additional input.…”

Section: Supplementary Informationmentioning

confidence: 99%

Transcriptomic analysis reveals differential gene expression, alternative splicing, and novel exons during mouse trophoblast stem cell differentiation

et al. 2020

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Background: Differentiation of mouse trophoblast stem cells (TSCs) to trophoblast giant cells (TGCs) has been widely used as a model system to study placental development and function. While several differentially expressed genes, including regulators of TSC differentiation, have been identified, a comprehensive analysis of the global expression of genes and splice variants in the two cell types has not been reported. Results: Here, we report~7800 differentially expressed genes in TGCs compared to TSCs which include regulators of the cell cycle, apoptosis, cytoskeleton, cell mobility, embryo implantation, metabolism, and various signaling pathways. We show that several mitotic proteins, including Aurora A kinase, were downregulated in TGCs and that the activity of Aurora A kinase is required for the maintenance of TSCs. We also identify hitherto undiscovered, celltype specific alternative splicing events in 31 genes in the two cell types. Finally, we also report 19 novel exons in 12 genes which are expressed in both TSCs and TGCs. Conclusions: Overall, our results uncover several potential regulators of TSC differentiation and TGC function, thereby providing a valuable resource for developmental and molecular biologists interested in the study of stem cell differentiation and embryonic development.

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NOSTRIN: A novel modulator of trophoblast giant cell differentiation

Cited by 20 publications

References 43 publications

MicroRNA regulation of murine trophoblast stem cell self-renewal and differentiation

MicroRNA regulation of murine trophoblast stem cell self-renewal and differentiation

Sequestration of eIF4A by angiomotin: A novel mechanism to restrict global protein synthesis in trophoblast cells

Transcriptomic analysis reveals differential gene expression, alternative splicing, and novel exons during mouse trophoblast stem cell differentiation

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