Negative regulators of Wnt signaling pathway SFRP1 and SFRP3 expression in preterm and term pathologic placentas

Partl, Jasenka Zmijanac; Karin, Valentina; Škrtić, Anita; Nikuševa-Martić, Tamara; Šerman, Alan; Mlinarec, Jelena; Ćurković‐Perica, Mirna; Vranić, Semir; Šerman, Ljiljana

doi:10.1080/14767058.2017.1359830

Cited by 10 publications

(8 citation statements)

References 27 publications

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“…WNT1 gene belongs to the WNT signaling pathway, which is involved in cell proliferation, development, and tumor progression. WNT signaling pathway inhibition could contribute to miscarriages and PTB, via decreasing trophoblast proliferation and invasion [42]. Notoriously, WNT2 gene, which is typically overexpressed in placenta, was not DE in our data.…”

Section: Discussionmentioning

confidence: 58%

Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth

Pereyra

Bertoni

Sosa

et al. 2018

Preprint

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15 16 Short title: Transcriptomic analysis of severe preterm birth 17 Key words: RNA-seq, preterm birth, gestational age, biomarkers 18 2 19Abstract 20 Preterm birth (PTB), defined as infant delivery before 37 weeks of completed gestation, results of 21 the interaction of both genetic and environmental components and constitutes a complex 22 multifactorial syndrome. Transcriptome analysis of PTB has proved challenging because of the 23 multiple causes of PTB and the numerous maternal and fetal gestational tissues that must interact 24 to facilitate parturition. A common pathway of labor and PTB may be the activation of fetal 25 membranes. In this work, chorioamnion membranes from severe preterm and term fetus were 26 analyzed using RNA sequencing. A total of 270 genes were differentially expressed (DE): 252 27 were up-regulated and 18 were down-regulated in the severe preterm compared to the term births. 28 We found great gene expression homogeneity in the control samples, and not in severe preterm 29 samples. In this work, we identified up-regulated pathways that were previously suggested as 30 leading to PTB like immunological and inflammatory paths. New pathways that were not 31 identified in preterm like the hemopoietic path appeared up-regulated in preterm membranes. A 32 group of 18 down-regulated genes discriminates between term and severe preterm cases. These 33 genes potentially characterize a severe preterm transcriptome pattern and therefore are candidate 34 genes for understanding the syndrome. Some of the down-regulated genes are involved in the 35 nervous system, morphogenesis (WNT-1, DLX5, PAPPA2) and ion channel complexes (KCNJ16, 36 KCNB1), making them good candidates as biomarkers of PTB.37 The identification of this DE gene pattern may help to develop a multi-gene disease classifier.38 These markers were generated in an admixtured South American population where PTB has a high 39 incidence. Since genetic background may impact differentially in different populations it is 40 mandatory to include populations like South American and African ones that are usually excluded 3 41 from high throughput approaches. These classifiers should be compared to those in other 42 populations to get a global landscape of PTB. 43 44 Introduction 45 Preterm birth (PTB), defined as the delivery of an infant before 37 weeks of completed gestation, 46 is a worldwide health problem and remains the leading cause of global perinatal morbidity and 47 mortality [1][2][3]. PTB is a complex, multifactorial syndrome comprised of multiple clinical 48 subtypes that can be defined as either 'spontaneous' or 'medically indicated' [4,5]. 70 % of PTB 49 cases are idiopathic; 5 % are due to the spontaneous onset of labor (sPTB) and the remaining 25 50 % are consequence of the preterm premature rupture of membranes (PPROM) [5,6]. PTB has also 51 been stratified according to gestational age (GA); neonates born between 24 and 33 weeks (severe 52 PTB) are at higher risk of death, and diseases later in life, than moderate PTB (GA betwee...

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Section: Discussionmentioning

confidence: 58%

Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth

Pereyra

Bertoni

Sosa

et al. 2018

Preprint

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“…We have previously shown increased activation of the SFRP family members, inhibitors of the Wnt signaling pathway, in pathological placentas from pregnancies with IUGR [ 9 ]. In addition, it has been found that mice with hypermethylated Wnt2 gene promoter have a lower birth weight (they are small for gestational age, SGA) [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Dishevelled family proteins (DVL1-3) expression in IUGR placentas

Sola

Šerman²,

Karin-Kujundžić

et al. 2020

Bosn J of Basic Med Sci

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Dishevelled family proteins (DVL1, DVL2, and DVL3) are cytoplasmic mediators involved in canonical and non-canonical Wnt signaling that are important in embryonic development. The role of DVL proteins in the placental tissue remains mostly unknown. In the current study, we explored the role of Dishevelled proteins in naturally invasive tissue, trophoblast. Formalin-fixed paraffin-embedded samples of 15 term placentas from physiologic term pregnancies and 15 term placentas from pregnancies complicated with intrauterine growth restrictions (IUGR) were used for the study. Expression levels of mRNA for DVL1, DVL2, and DVL3 in placentas were analyzed by quantitative real-time PCR (qRT-PCR). DVL1, DVL2, and DVL3 protein expression were semi-quantitatively analyzed using immunohistochemistry. The expression of DVL2 and DVL3 proteins was significantly higher in trophoblasts in placental villi from IUGR pregnancies compared with the control group of term placentas. In contrast, DVL3 protein expression was significantly higher in endothelial cells in placental villi from IUGR pregnancies compared with normal term placentas. The observed differences at protein levels between normal and IUGR placentas were not confirmed at the mRNA levels of DVL genes. Our data indicate the active involvement of DVL proteins in IUGR-related placentas. No significant changes were observed in DVL mRNA levels between the two groups of placentas. Further studies are required to explore the clinical relevance of these observations.

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“…On the other hand, expression of CTTNBP2 and NSF1 was downregulated in BeWo cells in which HAND1 was knocked down. CTTNBP2 has been shown to have a direct relationship with the WNT signaling pathway (Kelly et al, 2017 ), and downregulation in WNT signaling in the placenta has been associated with pathological pregnancies (Zmijanac Partl et al, 2018 ). Similarly, NFS1 is a gene that has an essential role in iron–sulfur cluster processing making it important for electron transport, enzyme catalysis, and regulation of gene expression as well is iron homeostasis (Brzoska et al, 2006 ).…”

Section: Discussionmentioning

confidence: 99%

HAND1 knockdown disrupts trophoblast global gene expression

Fresch

Courtney

Brockway

et al. 2023

Physiological Reports

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Congenital heart disease (CHD) affects nearly 1% of births annually, and CHD pregnancies carry increased risk of developing pathologies of abnormal placentation. We previously reported significant developmental impacts of disrupting Hand1, a gene associated with CHD, expression in placenta trophoblast and endothelial cells in multiple mouse models. In this study, we aimed to build upon this knowledge and characterize the mechanistic impacts of disrupting HAND1 on human placenta trophoblast and vascular endothelial cell gene expression. HAND1 gene expression was silenced in BeWo cells, a choriocarcinoma model of human cytotrophoblasts, (n = 3–9 passages) and isolated human placental microvascular endothelial cells (HPMVEC; n = 3 passages), with HAND1 siRNA for 96 h. Cells were harvested, mRNA isolated and RNA sequencing performed using the Illumina NextSeq 550 platform. Normalization and differential gene expression analyses were conducted using general linear modeling in edgeR packages. Statistical significance was determined using a log2 fold change of >1.0 or < −1.0 and unadjusted p‐value ≤0.05. Panther DB was used for overrepresentation analysis, and String DB for protein association network analysis. There was downregulation of 664 genes, and upregulation of 59 genes in BeWo cells with direct HAND1 knockdown. Overrepresentation analysis identified disruption to pathways including cell differentiation, localization, and cell projection organization. In contrast, only seven genes were changed with direct HAND1 knockdown in HPMVECs. Disruption to HAND1 expression significantly alters gene expression profile in trophoblast but not endothelial cells. This data provides further evidence that future studies on genetic perturbations in CHDs should consider the extra‐embryonic tissue in addition to the fetal heart.

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Negative regulators of Wnt signaling pathway SFRP1 and SFRP3 expression in preterm and term pathologic placentas

Abstract: Our findings indicate the active involvement of negative Wnt regulators SFRP1/SFRP3 in placental development and important role in pathology of pregnancy.

Cited by 10 publications

References 27 publications

Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth

Transcriptomic analysis of fetal membranes reveals pathways involved in preterm birth

Dishevelled family proteins (DVL1-3) expression in IUGR placentas

HAND1 knockdown disrupts trophoblast global gene expression

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