Alterted SLIT2/ROBO1 signalling is linked to impaired placentation of missed and threatened miscarriage in early pregnancy

Li, Ping; Shi, Yuxun; Shuai, Han-Lin; Cai, Yanzhen; Lu, Wenhui; Wang, Guang; Gao, Lufen; Wang, Lijing; Fan, Xiujun; Yang, Xuesong

doi:10.1111/his.13250

Cited by 16 publications

(13 citation statements)

References 24 publications

(48 reference statements)

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“…We detected association signals for SNPs in a region that encompassed SLIT2 and for SNPs in a region downstream of ROBO1 , which encodes the receptor for SLIT2. SLIT2 and ROBO1 encode proteins of the SLT2-ROBO1 signaling pathway; previous studies have indicated that this pathway is associated with different types of pregnancy complications, including preeclampsia [27,28], impaired placentation of missed and threatened miscarriage in early pregnancy [29], trophoblast invasion, and vascular remodeling during ectopic tubal pregnancy [29,30]. Our hypothesis-free GWAS study provides evidence that these genes have a role in another pregnancy complication, SPTB.…”

Section: Discussionmentioning

confidence: 60%

“…In addition to their functions in biogenesis of the placenta and maintenance of pregnancy, trophoblasts may participate in labor induction [43]. Two‐thirds of early pregnancy failures may present with reduced trophoblast invasion [29]. SLIT-ROBO signaling may play autocrine and/or paracrine roles in trophoblast functions, such as differentiation and invasion, by influencing the migration of trophoblastic cells [29,44].…”

Section: Discussionmentioning

confidence: 99%

“…Two‐thirds of early pregnancy failures may present with reduced trophoblast invasion [29]. SLIT-ROBO signaling may play autocrine and/or paracrine roles in trophoblast functions, such as differentiation and invasion, by influencing the migration of trophoblastic cells [29,44]. Thus, SLIT2-ROBO1 signaling may be involved in the pathogenesis of pregnancy failures via their effect on trophoblastic cell functions.…”

Section: Discussionmentioning

confidence: 99%

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Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2

et al. 2019

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Spontaneous preterm birth (SPTB) is the leading cause of neonatal death and morbidity worldwide. Both maternal and fetal genetic factors likely contribute to SPTB. We performed a genome-wide association study (GWAS) on a population of Finnish origin that included 247 infants with SPTB (gestational age [GA] < 36 weeks) and 419 term controls (GA 38–41 weeks). The strongest signal came within the gene encoding slit guidance ligand 2 ( SLIT2 ; rs116461311, minor allele frequency 0.05, p = 1.6×10 −6 ). Pathway analysis revealed the top-ranking pathway was axon guidance, which includes SLIT2 . In 172 very preterm-born infants (GA <32 weeks), rs116461311 was clearly overrepresented (odds ratio 4.06, p = 1.55×10 −7 ). SLIT2 variants were associated with SPTB in another European population that comprised 260 very preterm infants and 9,630 controls. To gain functional insight, we used immunohistochemistry to visualize SLIT2 and its receptor ROBO1 in placentas from spontaneous preterm and term births. Both SLIT2 and ROBO1 were located in villous and decidual trophoblasts of embryonic origin. Based on qRT-PCR, the mRNA levels of SLIT2 and ROBO1 were higher in the basal plate of SPTB placentas compared to those from term or elective preterm deliveries. In addition, in spontaneous term and preterm births, placental SLIT2 expression was correlated with variations in fetal growth. Knockdown of ROBO1 in trophoblast-derived HTR8/SVneo cells by siRNA indicated that it regulate expression of several pregnancy-specific beta-1-glycoprotein ( PSG ) genes and genes involved in inflammation. Our results show that the fetal SLIT2 variant and both SLIT2 and ROBO1 expression in placenta and trophoblast cells may be correlated with susceptibility to SPTB. SLIT2-ROBO1 signaling was linked with regulation of genes involved in inflammation, PSG genes, decidualization and fetal growth. We propose that this receptor-ligand couple is a component of the signaling network that promotes SPTB.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2

et al. 2019

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“…Often known as essential in implantation are numerous regulatory proteins recognized to play a key role in cancer cell invasion [29] .E-cad is found in humans in trophoblasts, and homophilic interaction between cytotrophoblast and endometrium are thought to be mediated through it. This may mean that E-cad involves in the embryo implantation initial stage [30] , and it is down-regulated in placental villi during early pregnancy in patients with spontaneous miscarriage may be regarded as one of risk factors of this condition [31] .However, no evidence exists to indicate whether or not the down-regulation of E-cad expression in villi or the up-regulation of E-cad expression in extravillous trophoblasts marks the beginning or the terminal stages of trophoblast differentiation in patients with missed and threatened miscarriage [32] . In our study, we evaluated the serum level of MycBP and E-cad and explored the correlation between these two biomarkers with this clinical condition.…”

Section: Introductionmentioning

confidence: 99%

Which one affect the other, Recurrent Pregnancy Loss or Serum Level of E?cadherin and c-MycBP

Zena Abdul-Ameer Mahdi,

Nadia M. Al-Hilli,

Maha F. Smaism

2021

Indian Journal of Forensic Medicine & Toxicology

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Recurrent pregnancy loss (RPL) is a foremost life event and a common pregnancy complication, which defined as losses of two or more pregnancies before 20 weeks of gestation. It affects approximately 1% -2% of couples trying to have children. To evaluate the potential role of cellular myelocytomatosis binding protein (c-MycBP) and epithelial cadherin (E-cad) serum level as biomarkers in maternal blood and focus on the similarity between tumour invasion and embryogenesis as phenomena by c-MycBP and E-cadherin. This case control study included 50 women with RPL (25 primary RPL and 25 secondary RPL) from three infertility clinics in Iraq. In addition to 50 control women with no history of RPL and at least one child birth. Both groups are matched in age and BMI. Blood sampling was done for all and protein level of c-Myc BP and E-cadherin were measured by ELISA Kit and analysis done according to the manufacturer recommendations. The result presented in this study showed a significant difference in c-MycBP level (p<0.001) and E-cadherin (p<0.001) between patients and control. A significant positive correlation has been found between these two biochemical markers (p <0.001, r=-0.39). The present study showed that decreasing both c-MycBP and E-cad serum level signpost possible hypothesis that these proteins participate in one way or another in RPL pathogenesis which affect cell proliferation and invasion. However, this binding protein transcription factor is a part of a coordinated network of various set of partners which need further studies in future. Taken together, additional studies are required to understand and clarify the importance of these biomarkers on this multifactorial condition.

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“…3 The most common factors contributing to the EM include cytogenetic defects of the conceptus, anatomical abnormalities, autoimmune disorders, infections, and endocrine and psychological factors. 4,5 Recent studies suggest that poor placentation and conceptus loss may result from key defects such as fetus abnormalities, primary trophoblast dysfunction, abnormal karyotype, 6 defective placental angiogenesis, 7 genetic aberration, elevated inflammatory cytokines level, 8,9 imbalance between trophoblastic apoptosis, 10 macroautophagy and hypoxic milieu. 11 The etiology of EM remains complex, and in approximately 50% of the cases, causes and molecular mechanisms continue to remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

High Level of APOA1 in Blood and Maternal Fetal Interface Is Associated With Early Miscarriage

et al. 2019

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Early miscarriage (EM) is one of the most devastating obstetrical complications globally affecting the quality of women's life. In the present study, we aimed to identify proteins that correlate with and could act as biomarkers for EM. We performed 2-dimensional gel electrophoresis in chorionic villi samples followed by mass spectrometry for identification of differential protein expression with EM. Proteomic studies detected a total 124 protein spots, out of which 83 spots were differentially expressed between EM and controls in chorionic villi samples. Matrix assisted laser desorbtion/ionization-time of flight (MALDI-TOF) mass spectrometry analysis revealed Apolipoprotein A1 (APOA1) to be the most upregulated protein in the EM group that was validated by Western blotting and Enzyme-linked immunosorbent assay (ELISA) . We found low but not statistically significant level of APOA1 on 21st day of menstruation in comparison to the 7th day. APOA1 level was observed to be the lowest in the first trimester. Hence, this study suggests that low APOA1 expression is critical in establishing pregnancy and elevated APOA1 expression in chorionic villi correlates with EM. Similar observation in serum samples suggests its potential as a marker for the risk of EM.

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Alterted SLIT2/ROBO1 signalling is linked to impaired placentation of missed and threatened miscarriage in early pregnancy

Abstract: SLIT2/ROBO1 signalling may regulate trophoblast differentiation and invasion causing restricting β-hCG production, shallow trophoblast invasion and inhibiting placental angiogenesis in missed and threatened miscarriage during the first trimester.

Cited by 16 publications

References 24 publications

Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2

Risk of spontaneous preterm birth and fetal growth associates with fetal SLIT2

Which one affect the other, Recurrent Pregnancy Loss or Serum Level of E?cadherin and c-MycBP

High Level of APOA1 in Blood and Maternal Fetal Interface Is Associated With Early Miscarriage

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