scholarly journals Fetal and trophoblast PI3Kp110α have distinct roles in regulating resource supply to the growing fetus

2018 ◽  
Author(s):  
Jorge Lopez-Tello ◽  
Vicente Perez-Garcia ◽  
Jaspreet Khaira ◽  
Laura C. Kusinski ◽  
Wendy N. Cooper ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Embryonic Stem ◽  
Prenatal Development ◽  
Complete Loss ◽  
Placental Development ◽  
Expression Of Genes ◽  
Transport Loss ◽  
Healthy Growth ◽  
Phosphoinositide 3 Kinase

AbstractPrevious studies suggest that the placental supply of nutrients to the fetus adapts according to fetal demand. However, the signaling events underlying placental adaptations remain largely unknown. Earlier work in mice has revealed that loss of the phosphoinositide 3-kinase p110α impairs feto-placental growth but placental nutrient supply is adaptively increased. Here we explore the role of p110α in the epiblast-derived (fetal) and trophoblast lineages of the conceptus in relation to feto-placental growth and placental development and transfer function. Using conditional gene manipulations to knock-down p110α either by ∼50% or ∼100% in the fetal lineages and/or trophoblast, this study shows that p110α in the fetus is essential for prenatal development and a major regulator of placental phenotype in mice. 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 also resulted in abnormal placental development, although fetuses were viable. However, in response to complete loss of trophoblast p110α, the placenta failed to transport sufficient amino acid to match fetal demands for growth. Using RNA-seq, we identified several genes downstream of p110α in the trophoblast that are important in adapting placental phenotype to support fetal growth. Further work using CRISPR/Cas9 genome targeting showed that loss of p110α differentially affects the expression of genes in trophoblast and embryonic stem cells. Our findings thus reveal important, but distinct roles for p110α signaling in the different compartments of the conceptus, which control fetal resource acquisition and ultimately affect healthy growth.One Sentence SummaryFetal and trophoblast p110α modify resource allocation

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

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jorge López-Tello ◽  
Vicente Pérez-García ◽  
Jaspreet Khaira ◽  
Laura C Kusinski ◽  
Wendy N Cooper ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Nutrient Transport ◽  
Embryonic Stem ◽  
Nutrient Supply ◽  
Complete Loss ◽  
Rna Seq ◽  
Placental Development ◽  
Transport Loss ◽  
Phosphoinositide 3 Kinase ◽  
Embryonic Death

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.

scholarly journals Trophectoderm-Specific Knockdown of LIN28 Decreases Expression of Genes Necessary for Cell Proliferation and Reduces Elongation of Sheep Conceptus

2020 ◽  
Vol 21 (7) ◽  
pp. 2549 ◽  
Author(s):  
Asghar Ali ◽  
Mark Stenglein ◽  
Thomas Spencer ◽  
Gerrit Bouma ◽  
Russell Anthony ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Critical Period ◽  
In Vitro Experiments ◽  
Placental Development ◽  
Expression Of Genes ◽  
Trophectoderm Cells ◽  
Successful Establishment

LIN28 inhibits let-7 miRNA maturation which prevents cell differentiation and promotes proliferation. We hypothesized that the LIN28-let-7 axis regulates proliferation-associated genes in sheep trophectoderm in vivo. Day 9-hatched sheep blastocysts were incubated with lentiviral particles to deliver shRNA targeting LIN28 specifically to trophectoderm cells. At day 16, conceptus elongation was significantly reduced in LIN28A and LIN28B knockdowns. Let-7 miRNAs were significantly increased and IGF2BP1-3, HMGA1, ARID3B, and c-MYC were decreased in trophectoderm from knockdown conceptuses. Ovine trophoblast (OTR) cells derived from day 16 trophectoderm are a useful tool for in vitro experiments. Surprisingly, LIN28 was significantly reduced and let-7 miRNAs increased after only a few passages of OTR cells, suggesting these passaged cells represent a more differentiated phenotype. To create an OTR cell line more similar to day 16 trophectoderm we overexpressed LIN28A and LIN28B, which significantly decreased let-7 miRNAs and increased IGF2BP1-3, HMGA1, ARID3B, and c-MYC compared to control. This is the first study showing the role of the LIN28-let-7 axis in trophoblast proliferation and conceptus elongation in vivo. These results suggest that reduced LIN28 during early placental development can lead to reduced trophoblast proliferation and sheep conceptus elongation at a critical period for successful establishment of pregnancy.

scholarly journals Low oxygen enhances trophoblast column growth by potentiating the extravillous lineage and promoting LOX activity

2019 ◽  
Author(s):  
Jenna Treissman ◽  
Victor Yuan ◽  
Jennet Baltayeva ◽  
Hoa T. Le ◽  
Barbara Castellana ◽  
...  
Keyword(s):  
Lysyl Oxidase ◽  
Atmospheric Oxygen ◽  
Extravillous Trophoblast ◽  
Low Oxygen ◽  
Placental Development ◽  
Trophoblast Differentiation ◽  
Expression Of Genes ◽  
Summary Statement ◽  
Insight Into

ABSTRACTEarly placental development and the establishment of the invasive trophoblast lineage take place within a low oxygen environment. However, conflicting and inconsistent findings have obscured the role of oxygen in regulating invasive trophoblast differentiation. In this study, the effect of hypoxic, normoxic, and atmospheric oxygen on invasive extravillous pathway progression was examined using a human placental explant model. Here, we show that exposure to low oxygen enhances extravillous column outgrowth and promotes the expression of genes that align with extravillous trophoblast (EVT) lineage commitment. By contrast, super-physiological atmospheric levels of oxygen promote trophoblast proliferation while simultaneously stalling EVT progression. Low oxygen-induced EVT differentiation coincided with elevated transcriptomic levels of lysyl oxidase (LOX) in trophoblast anchoring columns, where functional experiments established a role for LOX activity in promoting EVT column outgrowth. The findings of this work support a role for low oxygen in potentiating the differentiation of trophoblasts along the extravillous pathway. Additionally, these findings generate insight into new molecular processes controlled by oxygen during early placental development.Summary StatementLow oxygen promotes extravillous trophoblast differentiation

scholarly journals The Role of NFκB in Healthy and Preeclamptic Placenta: Trophoblasts in the Spotlight

2020 ◽  
Vol 21 (5) ◽  
pp. 1775 ◽  
Author(s):  
Brooke Armistead ◽  
Leena Kadam ◽  
Sascha Drewlo ◽  
Hamid-Reza Kohan-Ghadr
Keyword(s):  
Oxidative Stress ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Growth And Development ◽  
Protein Family ◽  
Growth Restriction ◽  
Placental Development ◽  
Critical Organ ◽  
And Oxidative Stress

The NFκB protein family regulates numerous pathways within the cell—including inflammation, hypoxia, angiogenesis and oxidative stress—all of which are implicated in placental development. The placenta is a critical organ that develops during pregnancy that primarily functions to supply and transport the nutrients required for fetal growth and development. Abnormal placental development can be observed in numerous disorders during pregnancy, including fetal growth restriction, miscarriage, and preeclampsia (PE). NFκB is highly expressed in the placentas of women with PE, however its contributions to the syndrome are not fully understood. In this review we discuss the molecular actions and related pathways of NFκB in the placenta and highlight areas of research that need attention

scholarly journals Kajian Pustaka: Kadar Brain Derived Neurotrophic Factor Mempengaruhi Berat Badan Lahir pada Bayi

2019 ◽  
Vol 19 (1) ◽  
pp. 152
Author(s):  
Yessi Ardiani ◽  
Defrin Defrin ◽  
Husna Yetti
Keyword(s):  
Fetal Growth ◽  
Neurotrophic Factor ◽  
Intrauterine Growth Restriction ◽  
Potential Role ◽  
Growth Disorders ◽  
Placental Development ◽  
Intrauterine Growth ◽  
Additional Information ◽  
Implantation Period

Brain Derived Neurotrhophic Factor (BDNF) is one of the proteins needed for the growth of neurons. During its development period BDNF plays a role in nerve growth, differentiation, repair, and survival of nerve cells. In addition, researchers from certain groups found that BDNF also had an important role during the implantation period, placental development and development of fetal growth. BDNF is known to have an important role in regulating angiogenesis needed for placental development. Because of this role, BDNF deficiency will cause disruption in placental growth which will eventually cause fetal growth disorders or Intrauterine growth restriction (IUGR). In recent years studies have shown that neurotrophins play an important role in the regulation of placental development and fetal growth. BDNF has been found to be expressed in large amounts in blastocysts which indicate the potential role of BDNF in implantation and development of the placenta. BDNF is also produced in the muscle tissue of one of them in the uterus precisely in the endometrium and myometrium. The discovery of the role of BDNF, is expected to be used as an indicator to assess the occurrence of growth disorders in the fetus as well as additional information about the etiology and pathophysiology of IUGR. Keywords: BDNF; IUGR; Neurotrophin

Placental-Specific Igf2 Deficiency Alters Developmental Adaptations to Undernutrition in Mice

Endocrinology ◽  
2011 ◽  
Vol 152 (8) ◽  
pp. 3202-3212 ◽  
Author(s):  
A. N. Sferruzzi-Perri ◽  
O. R. Vaughan ◽  
P. M. Coan ◽  
M. C. Suciu ◽  
R. Darbyshire ◽  
...  
Keyword(s):  
Amino Acid ◽  
Fetal Growth ◽  
Late Pregnancy ◽  
Nutrient Restriction ◽  
Nutrient Transfer ◽  
Wild Type ◽  
Functional Responses ◽  
Placental Transport ◽  
Phosphoinositide 3 Kinase

The pattern of fetal growth is a major determinant of the subsequent health of the infant. We recently showed in undernourished (UN) mice that fetal growth is maintained until late pregnancy, despite reduced placental weight, through adaptive up-regulation of placental nutrient transfer. Here, we determine the role of the placental-specific transcript of IGF-II (Igf2P0), a major regulator of placental transport capacity in mice, in adapting placental phenotype to UN. We compared the morphological and functional responses of the wild-type (WT) and Igf2P0-deficient placenta in WT mice fed ad libitium or 80% of the ad libitium intake. We observed that deletion of Igf2P0 prevented up-regulation of amino acid transfer normally seen in UN WT placenta. This was associated with a reduction in the proportion of the placenta dedicated to nutrient transport, the labyrinthine zone, and its constituent volume of trophoblast in Igf2P0-deficient placentas exposed to UN on d 16 of pregnancy. Additionally, Igf2P0-deficient placentas failed to up-regulate their expression of the amino acid transporter gene, Slc38a2, and down-regulate phosphoinositide 3-kinase-protein kinase B signaling in response to nutrient restriction on d 19. Furthermore, deleting Igf2P0 altered maternal concentrations of hormones (insulin and corticosterone) and metabolites (glucose) in both nutritional states. Therefore, Igf2P0 plays important roles in adapting placental nutrient transfer capacity during UN, via actions directly on the placenta and/or indirectly through the mother.

scholarly journals The potential role of the ERRγ pathway in placental dysfunction

Reproduction ◽  
2020 ◽  
Author(s):  
Zhiyong Zou ◽  
Karen Forbes ◽  
Lynda K. Harris ◽  
Alexander E P Heazell
Keyword(s):  
Fetal Growth ◽  
Therapeutic Interventions ◽  
Placental Development ◽  
Human Trophoblast ◽  
Altered Expression ◽  
Placental Dysfunction ◽  
And Function ◽  
Upstream Regulators ◽  
Estrogen Related Receptor

Normal placental development and function is of key importance to fetal growth. Conversely aberrations of placental structure and function are evident in pregnancy complications including fetal growth restriction (FGR) and preeclampsia. Although trophoblast turnover and function is altered in these conditions, their underlying aetiologies and pathophysiology remains unclear, which hampers development of therapeutic interventions. Here we review evidence that supports a role for Estrogen Related Receptor-gamma (ERRγ) in the development of placental dysfunction in FGR and preeclampsia. This relationship deserves particular consideration because ERRγ is highly expressed in normal placenta, is reduced in FGR and preeclampsia and its expression is altered by hypoxia, which is thought to result from deficient placentation seen in FGR and preeclampsia. Several studies have also found microRNA or other potential upstream regulators of ERRγ negatively influence trophoblast function which could contribute to placental dysfunction seen in FGR and preeclampsia. Interestingly, microRNAs regulate ERRγ expression in human trophoblast. Thus, if ERRγ is pivotally associated with the abnormal trophoblast turnover and function it may be targeted by microRNAs or other possible upstream regulators in the placenta. This review explores altered expression of ERRγ and upstream regulation of ERRγ-mediated pathways resulting in the trophoblast turnover, placental vascularisation, and placental metabolism underlying placental dysfunctions. This demonstrates that the ERRγ pathway merits further investigation as a potential therapeutic target in FGR and preeclampsia.

scholarly journals Ethanol consumption during gestation promotes placental alterations in IGF-1 deficient mice

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 1284
Author(s):  
Irene Martín-Estal ◽  
Oscar R Fajardo-Ramírez ◽  
Mario Bermúdez De León ◽  
Carolina Zertuche-Mery ◽  
Diego Rodríguez-Mendoza ◽  
...  
Keyword(s):  
Fetal Growth ◽  
Molecular Mechanisms ◽  
Ethanol Consumption ◽  
Placental Development ◽  
Intrauterine Environment ◽  
Female Mice ◽  
Acclimation Period ◽  
Placental Efficiency ◽  
Deficient Mice

Background: During pregnancy, the placenta is an extremely important organ as it secretes its own hormones, e.g. insulin-like growth factor 1 (IGF-1), to ensure proper intrauterine fetal growth and development. Ethanol, an addictive and widely used drug, has numerous adverse effects during pregnancy, including fetal growth restriction (FGR). To date, the molecular mechanisms by which ethanol triggers its toxic effects during pregnancy, particularly in the placenta, are not entirely known. For this reason, a murine model of partial IGF-1 deficiency was used to determine ethanol alterations in placental morphology and AAH expression. Methods: Heterozygous (HZ, Igf1+/-) female mice were given 10% ethanol during 14 days as an acclimation period and throughout pregnancy. HZ female mice given water were used as controls. At gestational day 19, pregnant dams were sacrificed, placentas were collected and genotyped for subsequent studies. Results: IGF-1 deficiency and ethanol consumption during pregnancy altered placental morphology, and decreased placental efficiency and aspartyl/asparaginyl β-hydroxylase (AAH) expression in placentas from all genotypes. No differences were found in Igf1, Igf2, Igf1r and Igf2r mRNA expression in placentas from all groups. Conclusions: IGF-1 deficiency and ethanol consumption throughout gestation altered placental development, suggesting the crucial role of IGF-1 in the establishment of an adequate intrauterine environment that allows fetal growth. However, more studies are needed to study the precise mechanism to stablish the relation between both insults.

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