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

López-Tello, Jorge; Pérez-García, Vicente; Khaira, Jaspreet; Kusinski, Laura C.; Cooper, Wendy N.; Andreani, Adam; Grant, Imogen; Liger, Edurne Fernandez de; Lam, Brian; Hemberger, Myriam; Sandovici, Ionel; Constância, Miguel; Sferruzzi‐Perri, Amanda N.

doi:10.7554/elife.45282

Cited by 39 publications

(41 citation statements)

References 85 publications

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“…The offspring can be homozygous placental CYP19Cre + ;mTOR flox/flox or CYP19Cre + ;TSC2 flox/flox CYP19Cre + ;TSC2 flox/wt (mTORHET Placenta or TSC2HET Placenta ) or CYP19Crewith mTOR flox/flox , mTOR flox/wt , TSC2 flox/flox , or TSC2 flox/wt (littermate control). As demonstrated by others, CYP19 was exclusively expressed in the placenta and not in the fetus(20,22). Ai6 (CAG-ZsGreen1) mice (herein referred to as CAG) utilizes a CAG system containing ZsGreen1 loxP-flanked GFP protein and used for lineage tracing.…”

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confidence: 99%

Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice

Akhaphong¹,

Baumann²,

Beetch³

et al. 2021

JCI Insight

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Fetal growth restriction, or low birthweight is a strong determinant for eventual obesity and Type 2 diabetes. Clinical studies suggest placental mechanistic target of rapamycin (mTOR) signaling regulate fetal birthweight and the metabolic health trajectory of the offspring. In the current study, we used genetic model with loss of placental mTOR function (mTORKO Placenta ) to test the direct role of mTOR signaling on birthweight and the metabolic health in the adult offspring. mTORKO Placenta animals displayed reduced placental area and total weight, as well as fetal bodyweight at embryonic day (e) 17.5. Birthweight and serum insulin levels were reduced; however, β-cell mass was normal in mTORKO Placenta newborns. Adult mTORKO Placenta offspring, under a metabolic high-fat challenge, displayed exacerbated obesity and metabolic dysfunction compared to littermate controls. Subsequently, we tested whether enhancing placental mTOR complex 1 (mTORC1) signaling, via genetic ablation of TSC2, in utero would improve glucose homeostasis in the offspring. Indeed, increased placental mTORC1 conferred protection from a diet-induced obesity in the offspring. In conclusion, placental mTORC1 serves as a mechanistic link between placental function and programming of obesity and insulin resistance in the adult offspring.

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confidence: 99%

Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice

Akhaphong¹,

Baumann²,

Beetch³

et al. 2021

JCI Insight

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“…It cannot be excluded that the downregulation of ACTC1 and PDLIM3 in the placenta may result in an insufficiency in substrate supply to the fetus. Nutrient supply below the demand prevents the fetus from achieving its genetic growth potential and leads to FGR [ 76 ]. A high lncRNA–gene co-expression coefficient (0.93) between ACTA2-AS1 and downregulated SULF1 (log 2 FC = −4.39) in ff-FGR was also detected.…”

Section: Discussionmentioning

confidence: 99%

Sex-Biased lncRNA Signature in Fetal Growth Restriction (FGR)

Lipka

Jastrzebski

Paukszto

et al. 2021

Cells

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Impaired fetal growth is one of the most important causes of prematurity, stillbirth and infant mortality. The pathogenesis of idiopathic fetal growth restriction (FGR) is poorly understood but is thought to be multifactorial and comprise a range of genetic causes. This research aimed to investigate non-coding RNAs (lncRNAs) in the placentas of male and female fetuses affected by FGR. RNA-Seq data were analyzed to detect lncRNAs, their potential target genes and circular RNAs (circRNAs); a differential analysis was also performed. The multilevel bioinformatic analysis enabled the detection of 23,137 placental lncRNAs and 4263 of them were classified as novel. In FGR-affected female fetuses’ placentas (ff-FGR), among 19 transcriptionally active regions (TARs), five differentially expressed lncRNAs (DELs) and 12 differentially expressed protein-coding genes (DEGs) were identified. Within 232 differentially expressed TARs identified in male fetuses (mf-FGR), 33 encompassed novel and 176 known lncRNAs, and 52 DEGs were upregulated, while 180 revealed decreased expression. In ff-FGR ACTA2-AS1, lncRNA expression was significantly correlated with five DEGs, and in mf-FGR, 25 TARs were associated with DELs correlated with 157 unique DEGs. Backsplicing circRNA processes were detected in the range of H19 lncRNA, in both ff- and mf-FGR placentas. The performed global lncRNAs characteristics in terms of fetal sex showed dysregulation of DELs, DEGs and circRNAs that may affect fetus growth and pregnancy outcomes. In female placentas, DELs and DEGs were associated mainly with the vasculature, while in male placentas, disturbed expression predominantly affected immune processes.

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“…Consistent with this, CREB1 is regulated by metabolic stimuli like glucose 79 and PLAG1 was pinpointed as a critical factor altered in women who developed a complicated pregnancy 80 . In addition, both PLAG1 and CREB1 have been reported to be dysregulated in mouse genetic models showing placental dysfunction and/or poor pregnancy outcome 81,82 . Thus, numerous transcription factors likely govern the endocrine function of the placenta and may have significance for understanding the pathogenesis of human pregnancy complications.…”

Section: Discussionmentioning

confidence: 99%

Unbiased placental secretome characterization identifies candidates for pregnancy complications

Napso

Zhao

Lligoña

et al. 2020

Preprint

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Pregnancy requires adaptation of maternal physiology to enable normal fetal development. These adaptations are driven, in part, by the production of placental hormones. Failures in maternal adaptation and placental function lead to pregnancy complications including abnormal birthweight and gestational diabetes. However, we lack information on the full identity of hormones secreted by the placenta that mediate changes in maternal physiology. This study used an unbiased approach to characterise the secretory output of mouse placental endocrine cells and examined whether these data could identify placental hormones that are important for determining pregnancy outcome in humans. Secretome and cell peptidome analyses were performed using mass spectrometry on cultured primary trophoblast and fluorescence-activated sorted endocrine cells from pregnant mouse dams, and a placenta secretome map containing 319 proteins was generated. Gene ontology analyses showed that a high proportion of placental secretome proteins are involved in metabolic and immune modulation, signalling and growth. The majority of proteins identified are also expressed by human placenta and several have been reported to be dysregulated in pregnancy complications. Moreover, in proof of concept studies, we found that the relative abundance of secreted placental proteins (sFLT1/MIF and ANGPT2/MIF ratios) was increased in women at 12 weeks of pregnancy, prior to diagnosis of gestational diabetes. Finally, we identified several transcription factors that may be important for controlling hormone production by the placenta and associate with pregnancy outcome. Thus, our observations suggest that analysis of the placental secretome could lead to the identification of new placental biomarkers of pregnancy complications.

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

Cited by 39 publications

References 85 publications

Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice

Placental mTOR complex 1 regulates fetal programming of obesity and insulin resistance in mice

Sex-Biased lncRNA Signature in Fetal Growth Restriction (FGR)

Unbiased placental secretome characterization identifies candidates for pregnancy complications

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