The differential impact of maternal age on heart, brain, face, and placental development
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ABSTRACT: Investigating the impact of maternal age on heart, brain, face, and placental development by using RNA-seq to compare these tissues at E10.5 from young vs. aged females
Project description:The mammalian placenta is both the physical interface between mother and fetus, and the source of endocrine signals that target the maternal hypothalamus, priming females for parturition, lactation and motherhood. Despite the importance of this connection, the effects of altered placental signaling on the maternal brain are understudied. Here, we show that placental dysfunction alters gene expression in the maternal brain, with the potential to affect maternal behavior. Using a cross between the house mouse and the Algerian mouse in which hybrid placental development is abnormal, we sequenced late gestation placental and maternal medial preoptic area transcriptomes and quantified differential expression and placenta-maternal brain co-expression between normal and hybrid pregnancies. The expression of Fmn1, Drd3, Caln1 and Ctsr was significantly altered in the brains of females exposed to hybrid placentas. Most strikingly, expression patterns of placenta-specific gene families and Drd3 in the brains of house mouse females carrying hybrid litters matched those of female Algerian mice, the paternal species in the cross. Our results indicate that the paternally-derived placental genome can influence the expression of maternal-fetal communication genes, including placental hormones, suggesting an effect of the offspring's father on the mother’s brain.
Project description:Advanced maternal age is a risk factor for neurodevelopmental disorders in offspring. The present study aimed to investigate differences in placental and fetal head gene expression between old and young C57BL6/J female mice. Conceptuses were collected at E12.5 and processed for transcriptomic mRNA gene expression microarray analyses. The most significant differences between old and young females were found in gene expression of the fetal heads (398 differentially expressed genes, DEG) as compared with the placenta (51 DEG).
Project description:Introduction: Advanced maternal age (AMA) increases the risk of pregnancy complications, in part due to impaired placentation. While exercise during pregnancy can improve outcomes, its potential to mitigate the effects of AMA has not been investigated. We evaluated the impact of exercise in a mouse model of AMA. Methods: Females were paired with males at 9 or 34 weeks of age, with one group of aged females having access to running wheels four weeks prior to and during pregnancy. Pregnant females (N = 19 per group) were collected at gestational day (GD) 11.5. Placentas were collected for RNA sequencing (N = 17-20 per group). Results: Aged females without access to running wheels had heavier fat depots, while those with access to running wheels did not differ from young females. The number of viable conceptuses and fetal size were lower in both groups of aged females. Hundreds of genes were differentially expressed between young females and each of the aged groups, but only one gene was affected by access to running wheels. The placental transcriptomes of both aged groups were more similar to that of young mice at GD 10.5 than to young mice at GD 11.5, suggesting delayed placental development. Conclusions: Our model reproduced previously-reported effects of age on fetal development and placental transcriptomics, but these were not mitigated by increased voluntary locomotor activity, despite a reduction in adiposity. Remarkably, increased voluntary locomotor activity had almost no effects on placental gene expression in aged mice.
Project description:The pregnant decidua is infiltrated by many immune cells which are thought to originate in the bone marrow (BM) promoting pregnancy. CXCR4 is a key regulator of the development of NK cells and dendritic cells, both of which play an important role in early placental development and immune tolerance at the maternal-fetal interface. However, the role of CXCR4 in pregnancy is not well understood. To generate tamoxifen-inducible CXCR4 knockout mice, we used the Cre/LoxP tamoxifen-inducible system. For animal experiments, Cre+/CXCR4fl/fl mice and their Cre-/CXCR4fl/fl littermates were used. After tamoxifen treatment, we refer to Cre-/CXCR4fl/wt mice as WT (wild type), and Cre+/CXCR4fl/null mice as CXCR4 KO (knockout). For adoptive bone marrow transplant (BMT) experiments, BMT was performed from either WT GFP transgenic male donor mice into WT or CXCR4 KO females, or from CXCR4 KO male donors into CXCR4 KO females as negative control. Collectively, our study found an important role for maternal CXCR4 expression in immune cell function, placental development and pregnancy maintenance.
Project description:To explore the influence of maternal choline intake on placental gene expression, we employed whole genome microarray expression profiling to identify genes that were differentially expressed in placental tissues obtained from women consuming two different doses (480 vs. 930 mg/d) of choline throughout the third trimester of pregnancy. Healthy third trimester (gestational week 26-29) pregnant women were randomized to a 12-week choline controlled feeding study. The participants consumed either 480 (n=6) or 930 (n=6) mg choline/d. Full thickness placental samples were collected at delivery to extract RNA and perform the arrays. Healthy third trimester (gestational week 26-29) pregnant women were randomized to a 12-week choline controlled feeding study. The participants consumed either 480 (n=6) or 930 (n=6) mg choline/d for 12 weeks. Placental samples were obtained at delivery
Project description:Noninvasive prenatal diagnosis currently used does not achieve desirable levels of sensitivity and specificity. Recently, fetal methylated DNA biomarkers in maternal whole blood have been explored for noninvasive prenatal detection. However, such efforts cover only chromosomal aneuploidy; fetal methylated DNA biomarkers for detecting single-gene disease remain to be discovered. To address this issue, we systematically screened significantly hypermethylated genes in fetal tissues compared with maternal blood for noninvasive prenatal diagnosis of various inherited diseases. First, Methylated-CpG island recovery assay combined with CpG island array was performed in four maternal peripheral bloods and their corresponding placental tissues. Subsequently, direct bisulfite sequencing and combined bisulfite restriction analysis (COBRA) were carried out to validate the reliability of methylation microarray analysis. As results, 310 significantly hypermethylated genes in fetal tissues were detected by microarray. Two of five randomly selected hypermethylated genes detected by microarray were confirmed to be hypermethylated in fetal tissue samples by direct bisulfite sequencing. All four randomly selected hypermethylated genes detected by microarray were confirmed to be hypermethylated in five independent amniotic fluid samples and five independent chorionic villus samples from 10 pregnant women by CORBA. In conclusions, We found a lot of hypermethylated genes and methylation sites in fetal tissues, some of which have great potential to be developed into molecular markers for noninvasive prenatal diagnosis of monogenic disorders. Further clinical study is warranted to confirm these findings. Paired experiments, placental tissues vs. maternal peripheral bloods. Biological replicates: 4 placental tissues and 4 correspoding maternal peripheral bloods.
Project description:We report that depletion of the maternal microbiota results in abberant placental development in mice - these data show gene expression changes in E14.5 placental labyrinth samples from microbiota-depleted dams and controls.