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Fetal and trophoblast PI3K p110α have distinct roles in regulating resource supply to the growing fetus

ABSTRACT: Using RNA-seq we identified several genes downstream of p110α in the trophoblast that are important in adapting placental phenotype to support fetal growth.

ORGANISM(S): Mus musculus

PROVIDER: GSE126046 | GEO | 2019/07/25

REPOSITORIES: GEO

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Fetal and trophoblast PI3K p110α have distinct roles in regulating resource supply to the growing fetus in mice.

Project description:Studies suggest that placental nutrient supply adapts according to fetal demands. However, signaling events underlying placental adaptations remain unknown. Here we demonstrate that phosphoinositide 3-kinase p110α in the fetus and the trophoblast interplay to regulate placental nutrient supply and fetal growth. Complete loss of fetal p110α caused embryonic death, whilst heterozygous loss resulted in fetal growth restriction and impaired placental formation and nutrient transport. Loss of trophoblast p110α resulted in viable fetuses, abnormal placental development and a failure of the placenta to transport sufficient nutrients to match fetal demands for growth. Using RNA-seq we identified genes downstream of p110α in the trophoblast that are important in adapting placental phenotype. Using CRISPR/Cas9 we showed loss of p110α differentially affects gene expression in trophoblast and embryonic stem cells. Our findings reveal important, but distinct roles for p110α in the different compartments of the conceptus, which control fetal resource acquisition and growth.

| S-EPMC6634971 | biostudies-literature

Fetal and trophoblast PI3K p110α have distinct roles in regulating resource supply to the growing fetus

Project description:Fetal and trophoblast PI3K p110α have distinct roles in regulating resource supply to the growing fetus

| PRJNA520850 | ENA

p110α of PI3K is Indispensable for Quiescence Exit in Adult Muscle Satellite Cells

Project description:Adult muscle stem cells (MuSC) are quiescent with a localization between myofibers and basal lamina. Upon injury, MuSC exit quiescence, reenter cell cycle, expand and differentiate for muscle regeneration. By using genetic mouse model, we identified p110α/mTORC1 signaling as a indispensable pathway that permits quiescence exit and cell cycle reentry. In order to dig out the downstream effectors, we compared the transcriptome of freshly isolated MuSC from Ctrl (p110α-f/+:R26-YFP/YFP:Pax7-CreER/CreER) to MuSC-specific p110α-null (iKO, p110α-f/f:R26-YFP/YFP:Pax7-CreER/CreER) mice by RNA-sequencing, and AP1 target genes were dramatically down-regulated in iKO MuSC. Restoration of Jun could significantly rescue the cell cycle reentry defect in iKO MuSC. In summary, we provided a p110α/mTORC1/Jun axis required for quiecence exit and cell cycle reentry of MuSC.

2018-02-25 | GSE109472 | GEO

Targeting the Phosphoinositide 3-Kinase p110α Isoform Impairs Cell Proliferation, Survival and Tumor Growth in Small Cell Lung Cancer

Project description:Purpose: The phosphoinositide 3-kinase (PI3K) pathway is fundamental for cell proliferation and survival and is frequently altered and activated in neoplasia, including carcinomas of the lung. In this study we investigated the potential of targeting the catalytic class IA PI3K isoforms in small cell lung cancer (SCLC), which is the most aggressive of all lung cancer types. Experimental Design: The expression of PI3K isoforms in patient specimens was analyzed. The effects on SCLC cell survival and downstream signaling were determined following PI3K isoform inhibition by selective inhibitors or down-regulation by small interfering RNA. Results: Over-expression of the PI3K isoforms p110α and p110β was shown by immunohistochemistry in primary SCLC tissue samples. Targeting the PI3K p110α with RNA interference (RNAi) or selective pharmacological inhibitors resulted in strongly affected cell proliferation of SCLC cells in vitro and in vivo, while targeting p110β was less effective. Inhibition of p110α also resulted in increased apoptosis and autophagy, which was accompanied by decreased phosphorylation of Akt and components of the mammalian target of rapamycin (mTOR) pathway, such as the ribosomal S6 protein, and the eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1). A DNA microarray analysis revealed that p110α inhibition profoundly affected the balance of pro- and anti-apoptotic Bcl-2 family proteins. Finally, p110α inhibition led to impaired SCLC tumor formation and vascularization in vivo. Conclusion: Together our data demonstrate the key involvement of the PI3K isoform p110α in multiple tumor-promoting processes in SCLC.

2012-12-01 | GSE40564 | GEO

p110α of PI3K is Indispensable for Quiescence Exit in Adult Muscle Satellite Cells

Project description:p110α of PI3K is Indispensable for Quiescence Exit in Adult Muscle Satellite Cells

| PRJNA431162 | ENA

Expression data from WT, p110α-/-, p110δ-/-, and p110αδ double knockout HSC and LMPP hematopoietic populations

Project description:Many cytokines and chemokines that are important in hematopoiesis activate the phosphatidylinositol 3-kinase kinase(PI3K) signaling pathway. Because this pathway is frequently mutated and activated in cancer, PI3K inhibitors have been developed for the treatment of several malignancies, and are now being tested in the clinic in combination with chemotherapy. However, the role of PI3K in adult hematopoietic stem cells (HSCs), particularly during hematopoietic stress, is still unclear. To understand the molecular mechanisms of how p110α and p110δ regulate the HSC and progenitor stress response, we examined the effects of p110α and p110δ deletion on gene expression in hematopoietic stem cells (HSCs) and lymphoid-primed multipotential progenitors (LMPPs).

2019-06-06 | GSE118053 | GEO

HDX analysis of PI3K oncogenic mutants

Project description:We used Hydrogen-Deuterium Exchange Mass Spectrometry (HDX-MS) to examine the dynamic structural changes caused by oncogenic mutations. We performed HDX-MS comparing the full-length complex against the catalytic core which suggest that addition of pY leads to mixed two state population where the state 1 consists of iSH2 bound p110α and the state 2 consists of p110α where the iSH2 is completely disengaged.Therefore, we propose that the non-kinase domain mutations push the equilibrium towards state 2 leading to enhanced enzyme activity.We also propose that the kinase domain mutations lead to the re-orientation of the c-terminal tail leading to exposure of the activation loop and enhanced membrane binding.

2023-02-22 | PXD031080 | Pride

Deciphering the function of Angiomotin in trophoblast cells

Project description:Trophectoderm-specific expression of Angiomotin (AMOT) in pre-implantation embryos followed by its unique expression in the post-implantation ectoplacental cone that harbors the trophoblast stem cell niche prompted our investigation on the function of AMOT in trophoblast cells. Using the in vitro trophoblast stem cell culture model, we established differentiation dependent up-regulation of AMOT expression in trophoblast cells. To understand the function of AMOT in trophoblast cells mass spectrometry-based proteomic analysis was employed to identify the AMOT interactome within the trophoblast proteome. This approach utilized immunoprecipitation of endogenous AMOT followed by fractionation on SDS-PAGE and subsequently subjecting the tryptic digested excised gel bands to mass spectrometry.

2021-11-03 | PXD019391 | Pride

scRNA-seq and snucRNA-seq of human primary trophoblast organoids (PTO) and trophoblast stem cells (TSCs) differentiation into extravillous trophoblast organoids (EVTs)

Project description:This study aims to compare in vivo human trophoblast differentiation into EVTs to different in vitro trophoblast organoids using single-cell and single-nuclei RNA sequencing. The study includes two type of systems: human primary trophoblast organoids (PTO) and trophoblast stem cells (TSCs). Trophoblast stem cell (TSC) lines BTS5 and BTS11 derived by Okae and colleagues were grown as described previously (Okae et al. 2018) and together with EVT media. Primary trophoblast organoids (PTO) were grown and differentiated into EVT as previously described by Turco & Sheridan (Turco et al 2018; Sheridan et al 2020). This study shows that the main regulatory programs mediating EVT invasion in vivo are preserved in in vitro models of EVT differentiation from primary trophoblast organoids and trophoblast stem cells.

2023-02-09 | E-MTAB-12650 | biostudies-arrayexpress

Human embryo and trophoblast proteome

Project description:Comprehensive quantitative proteomic study of human pre-implantation embryo stages reveal dynamic proteome landscape from M2, 8-cell and blastocyst stage, and during trophoblast stem cell (TS) differentiation. Identified key factors in early human embryos and lineage-specific trophoblast proteome profiles, correlated with transcriptomic analyses. This direct proteomic analysis provides a comprehensive analysis of the dynamic protein expression in human embryos during pre-implantation development and a powerful resource to enable further mechanistic studies on human trophoblast development and function.

2023-07-05 | MSV000092349 | MassIVE

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