p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction

Kohli, Shruti; Hoffmann, Juliane; Lochmann, Franziska; Markmeyer, Paulina; Huebner, Hanna; Fahlbusch, Fabian; Al‐Dabet, Moh’d Mohanad; Gadi, Ihsan; Manoharan, Jayakumar; Löttge, Michael; Zenclussen, Ana Claudia; Aharon, Anat; Brenner, Benjamin; Shahzad, Khurrum; Ruebner, Matthias; Isermann, Berend

doi:10.1038/cddis.2017.127

Cited by 16 publications

(11 citation statements)

References 42 publications

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“…Next, we tested whether CREB-binding proteins are required for CGB expression. Administration of C646, a selective inhibitor of CBP and p300 [16], significantly impaired forskolin-induced CGB expression in BeWo cells by 57.1% after 24 h (Fig. 5e).…”

Section: Creb-binding Proteins Are Required For Efficient βHcg Synthesismentioning

confidence: 94%

Platelet-derived factors impair placental chorionic gonadotropin beta-subunit synthesis

et al. 2019

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During histiotrophic nutrition of the embryo, maternal platelets may be the first circulating maternal cells that find their way into the placental intervillous space through narrow intertrophoblastic gaps within the plugs of spiral arteries. Activation of platelets at the maternal-fetal interface can influence trophoblast behavior and has been implicated in serious pregnancy pathologies. Here, we show that platelet-derived factors impaired expression and secretion of the human chorionic gonadotropin beta-subunit (βhCG) in human first trimester placental explants and the trophoblast cell line BeWo. Impaired βhCG synthesis was not the consequence of hampered morphological differentiation, as assessed by analysis of differentiation-associated genes and electron microscopy. Platelet-derived factors did not affect intracellular cAMP levels and phosphorylation of CREB, but activated Smad3 and its downstream-target plasminogen activator inhibitor (PAI)-1 in forskolin-induced BeWo cell differentiation. While TGF-β type I receptor inhibitor SB431542 did not restore impaired βhCG production in response to platelet-derived factors, Smad3 inhibitor SIS3 interfered with CREB activation, suggesting an interaction of cAMP/CREB and Smad3 signaling. Sequestration of transcription co-activators CBP/p300, known to bind both CREB and Smad3, may limit βhCG production, since CBP/p300 inhibitor C646 significantly restricted its forskolin-induced upregulation. In conclusion, our study suggests that degranulation of maternal platelets at the early maternal-fetal interface can impair placental βhCG production, without substantially affecting morphological and biochemical differentiation of villous trophoblasts. Key messages & Maternal platelets can be detected on the surface of the placental villi and in intercellular gaps of trophoblast cell columns from gestational week 5 onwards. & Platelet-derived factors impair hCG synthesis in human first trimester placenta. & Platelet-derived factors activate Smad3 in trophoblasts. & Smad3 inhibitor SIS3 interferes with forskolin-induced CREB signaling. & Sequestration of CBP/p300 by activated Smad3 may limit placental hCG production.

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Section: Creb-binding Proteins Are Required For Efficient βHcg Synthesismentioning

confidence: 94%

Platelet-derived factors impair placental chorionic gonadotropin beta-subunit synthesis

et al. 2019

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“…The PPAR signaling pathway also plays a role, as Pparg null trophoblast cells fail to undrego terminal syncytium formation, which disrupts the integrity of the vascular exchange interface and restricts growth of the fetus ( 78 , 79 ). Members of the PPAR family, as well as GCM1 and its antagonist NFE2 have been implicated in human IUGR placentas ( 80 – 82 ), demonstrating that abnormal differentiation of the villous trophoblast, especially of the syncytiotrophoblast layer, also contributes to placental insufficiency and IUGR in humans.…”

Section: Placental Structures Linked To Embryonic Growthmentioning

confidence: 99%

“…Although fetal growth in Gcm1 +/− conceptuses is not affected, wild-type females carrying Gcm1 +/− conceptuses develop late gestational hypertension similar to what is seen in pre-eclampsia patients. Human placentas from IUGR pregnancies express reduced levels of NFE2 , leading to upregulation of GCM1 and excessive development of the syncytium ( 82 ), suggesting that similar molecular pathways operate in the establishment of the human placental IHM and may contribute to IUGR when disrupted.…”

Section: Placental Structures Linked To Embryonic Growthmentioning

confidence: 99%

Regulation of Placental Development and Its Impact on Fetal Growth—New Insights From Mouse Models

2018

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The placenta is the chief regulator of nutrient supply to the growing embryo during gestation. As such, adequate placental function is instrumental for developmental progression throughout intrauterine development. One of the most common complications during pregnancy is insufficient growth of the fetus, a problem termed intrauterine growth restriction (IUGR) that is most frequently rooted in a malfunctional placenta. Together with conventional gene targeting approaches, recent advances in screening mouse mutants for placental defects, combined with the ability to rapidly induce mutations in vitro and in vivo by CRISPR-Cas9 technology, has provided new insights into the contribution of the genome to normal placental development. Most importantly, these data have demonstrated that far more genes are required for normal placentation than previously appreciated. Here, we provide a summary of common types of placental defects in established mouse mutants, which will help us gain a better understanding of the genes impacting on human placentation. Based on a recent mouse mutant screen, we then provide examples on how these data can be mined to identify novel molecular hubs that may be critical for placental development. Given the close association between placental defects and abnormal cardiovascular and brain development, these functional nodes may also shed light onto the etiology of birth defects that co-occur with placental malformations. Taken together, recent insights into the regulation of mouse placental development have opened up new avenues for research that will promote the study of human pregnancy conditions, notably those based on defects in placentation that underlie the most common pregnancy pathologies such as IUGR and pre-eclampsia.

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“… 9 , 10 Moreover, IUGR is associated with an increased risk of fetal-originated metabolic syndrome and cardiovascular disease. 10 , 11 , 12 Previous studies 7 , 13 , 14 have reported that placental insufficiency, intrauterine infection, fetal chromosome anomalies, gestational hypertension, and preeclampsia are risk factors for IUGR. However, the etiopathology of IUGR has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Association of Elevated Maternal Serum Total Bile Acids With Low Birth Weight and Intrauterine Fetal Growth Restriction

Song

Chen²,

Chen

et al. 2021

JAMA Netw Open

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IMPORTANCE Bile acids play essential roles in metabolic modulation. Excessive serum total bile acid (sTBA) levels during pregnancy are associated with adverse perinatal outcomes; however, their association with the risk of intrauterine growth restriction (IUGR) remains unclear. OBJECTIVE To investigate the association between maternal sTBA concentration during pregnancy and the risk of IUGR. DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study included pregnant individuals who delivered live singleton neonates and had regular antenatal examination records available at a hospital-based center in Shanghai, China, from 2014 to 2018. Data were analyzed from July to November 2020. EXPOSURES Maternal sTBA concentration during pregnancy. MAIN OUTCOMES AND MEASURES Fetal birth weight and probability of low birth weight (LBW) and IUGR. RESULTSThis study included 68 245 singleton pregnancies with live births for analysis. The mean (SD) age of the pregnant individuals was 30.5 (3.8) years, 67 168 patients (98.4%) were Han, and 50 155 (73.5%) were nulliparous. Nonlinear regression models suggested that there was an inverted J-shaped association between maternal sTBA level during pregnancy and fetal birth weight, with a steep decrease in birth weight at high sTBA levels (estimated mean [SE] birth weight for sTBA of 40.8 ug/mL, 2879 [39.9] g) and greater birth weights at lower sTBA levels (estimated mean [SE] birth weight for sTBA 0.4 μg/mL, 3290 [3.9] g; and for 4.1 μg/mL, 3334 [1.6] g). Lower birth weight and a higher incidence of IUGR were observed in patients with gestational hypercholanemia (sTBA Ն4.08 μg/mL) compared with those without gestational hypercholanemia (birth weight: estimated adjusted mean [SE], 3309 [3.32] vs 3338 [0.80] g; P = .005; incidence of IUGR: 62 of 4467 [1.4%] vs 312 of 63 778 [0.5%]; P < .001). Moreover, compared with patients with sTBA concentrations of less than 4.08 μg/mL, those with gestational hypercholanemia had an increased risk of LBW (adjusted odds ratio [aOR], 1.29; 95% CI, 1.09-1.53) and IUGR (aOR, 2.18; 95% CI, 1.62-2.91). In addition, there was an additive interaction between hypertensive disorders in pregnancy (HDP) and hypercholanemia on LBW and IUGR risk. The highest risks of LBW and IUGR were found in pregnant individuals with both HDP and hypercholanemia compared with those with normotensive pregnancies with sTBA concentrations less than 4.

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p45 NF-E2 regulates syncytiotrophoblast differentiation by post-translational GCM1 modifications in human intrauterine growth restriction

Cited by 16 publications

References 42 publications

Platelet-derived factors impair placental chorionic gonadotropin beta-subunit synthesis

Platelet-derived factors impair placental chorionic gonadotropin beta-subunit synthesis

Regulation of Placental Development and Its Impact on Fetal Growth—New Insights From Mouse Models

Association of Elevated Maternal Serum Total Bile Acids With Low Birth Weight and Intrauterine Fetal Growth Restriction

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