Maternal Immune Activation Disrupts Proteostasis in the Fetal Brain
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA623564 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11497609.fastq.gz | Fastqsanger.gz | |||
| SRR11497610.fastq.gz | Fastqsanger.gz | |||
| SRR11497611.fastq.gz | Fastqsanger.gz | |||
| SRR11497612.fastq.gz | Fastqsanger.gz | |||
| SRR11497613.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 122 |
Similar Datasets
Project description:Maternal infection and inflammation during pregnancy is associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon. We leveraged single-cell RNA sequencing to profile transcriptional changes in the rodent fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis, and stress signaling. We found that MIA specifically activated the integrated stress response (ISR) in male, but not female, MIA offspring, thereby reducing global mRNA translation and altering nascent proteome synthesis. Moreover, genetic blockade of ISR activation rescued the social behavior phenotype in MIA male offspring. Our data suggest that therapeutic targeting of the ISR may be beneficial in reducing maternal inflammation-associated neurodevelopmental disorders.
2020-11-09 | GSE148237 | GEO
Project description:Maternal infection and inflammation during pregnancy are associated with neurodevelopmental disorders in offspring, but little is understood about the molecular mechanisms underlying this epidemiologic phenomenon. Here, we leveraged single-cell RNA sequencing to profile transcriptional changes in the mouse fetal brain in response to maternal immune activation (MIA) and identified perturbations in cellular pathways associated with mRNA translation, ribosome biogenesis and stress signaling. We found that MIA activates the integrated stress response (ISR) in male, but not female, MIA offspring in an interleukin-17a-dependent manner, which reduced global mRNA translation and altered nascent proteome synthesis. Moreover, blockade of ISR activation prevented the behavioral abnormalities as well as increased cortical neural activity in MIA male offspring. Our data suggest that sex-specific activation of the ISR leads to maternal inflammation-associated neurodevelopmental disorders.
| S-EPMC7854524 | biostudies-literature
Project description:Activation of the maternal immune system during pregnancy can fetal development, which can lead to postnatal susceptibility to a wide range of diseases, including cardiovascular, metabolic and psychiatric disorders. During maternal immune activation (MIA), the maternal body must balance its ressources between mounting an immune response and investing resources into continued metabolism and growth : both essential for survival of the fetus and a successful pregnancy. How the placenta responds to MIA over time and how it can protect the fetus is not well understood, and neither are the fetal consequences of MIA. Here, we characterised the response to an induced acute inflammation in maternal lungs over time across maternal and fetal organs, using a combination of omics-methods, imaging and integrative computational analysis. We found that the placenta, unlike other maternal organs, did not react by inducing a typical inflammatory response, but instead initially induced genes associated to strengthen tissue integrity and simultaneously reduced growth to prevent exposure to potential infections. Afterwards, a return to homeostasis was observed, with heightened biosynthesis and expression of endoplasmic reticulum (ER) stress genes. This mechanism likely protects the fetus from inflammation, as we observed no immune response in the fetal liver transcriptome. Instead, we observed metabolic adaptations in the fetus, including a release of docosahexaenoic acid (DHA) Notably, DHA has a crucial function for fetal brain development , and levels of triglyceride and phosphatidylcholine lipids that are necessary for transportation of DHA to the brain were also increased. This metabolic response is likely a combination of the placental MIA response and temporary maternal fasting, caused by MIA-induced fever and lack of nutrient intake. Our study shows, for the first time, the temporal and systemic response to MIA in lungs across maternal and fetal organs.
2024-06-13 | PXD039402 | Pride
Project description:Maternal over- and undernutrition in pregnancy plays a critical role in fetal brain development and function. The effects of different maternal diet compositions on intrauterine programming of the fetal brain in the absence of maternal obesity or maternal undernutrition is a lesser-explored area. The goal of this study was to investigate the impact of two different maternal diets on fetal brain gene expression signatures, fetal/neonatal growth, and neonatal behavior in a mouse model. Female C57Bl/6J mice were fed one of two commercially-available chow diets (pelleted vs. powdered) with differing micronutrient and carbohydrate compositions throughout pregnancy and lactation. The powdered chow diet was richer in carbohydrates and lower in micronutrients than the pelleted chow diet, among other differences. On embryonic day 15.5, embryos were weighed and measured. Fetal brains were snap frozen. RNA was extracted from fetal forebrains for five fetuses per diet group and hybridized to whole genome expression microarrays. Functional analyses identified significant upregulation of canonical pathways and upstream regulators involved in cell cycle regulation, synaptic plasticity, and sensory nervous system development in the fetal brain, and significant downregulation of pathways related to cell and embryo death. Pathways related to DNA damage response, humoral and cell-mediated immune response, carbohydrate and lipid metabolism, small molecule biosynthesis, and amino acid metabolism were also dysregulated. Maternal dietary content is an important variable for researchers evaluating fetal brain development and offspring behavior to consider. Selection of a chow diet matched for micronutrients is crucial to avoid unexpected or undesired effects on offspring brain development and behavior.
2019-12-06 | GSE133525 | GEO
Project description:In utero infection and maternal inflammation can adversely impact fetal brain development. Maternal systemic illness, even in the absence of direct fetal central nervous system infection, is associated with an increased risk of autism and schizophrenia in affected offspring. The cell types mediating the response of the fetal brain to maternal inflammation are largely unknown, hindering the development of therapies to prevent and treat adverse neuropsychiatric outcomes. Here, we show that microglia are enriched for expression of receptors for relevant pathogens and cytokines throughout embryonic development.
2024-05-07 | GSE225464 | GEO
Project description:In utero infection and maternal inflammation can adversely impact fetal brain development. Maternal systemic illness, even in the absence of direct fetal central nervous system infection, is associated with an increased risk of autism and schizophrenia in affected offspring. The cell types mediating the response of the fetal brain to maternal inflammation are largely unknown, hindering the development of therapies to prevent and treat adverse neuropsychiatric outcomes. Here, we show that microglia are enriched for expression of receptors for relevant pathogens and cytokines throughout embryonic development.
2024-05-07 | GSE225430 | GEO
Project description:“Dysbiosis" of the maternal gut microbiome, in response to environmental challenges such as infection, altered diet and stress during pregnancy, has been increasingly associated with abnormalities in offspring brain function and behavior. However, whether the maternal gut microbiome regulates neurodevelopment in the absence of environmental challenge remains unclear. In addition, whether the maternal microbiome exerts such influences during critical periods of embryonic brain development is poorly understood. Here we investigate how depletion, and selective reconstitution, of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibit widespread transcriptomic alterations in the fetal brain relative to conventionally-colonized controls, with reduced expression of several genes involved in axonogenesis. In addition, embryos from microbiome-depleted mothers exhibit deficient thalamocortical axons and impaired thalamic axon outgrowth in response to cell-extrinsic guidance cues and growth factors. Consistent with the importance of fetal thalamocortical axonogenesis for shaping neural circuits for sensory processing, restricted depletion of the maternal microbiome from pre-conception through mid-gestation yields offspring that exhibit tactile hyposensitivity in select sensorimotor behavioral tasks. Gnotobiotic colonization of antibiotic-treated dams with a limited consortium of spore-forming bacteria indigenous to the gut microbiome prevents abnormalities in fetal brain gene expression, fetal thalamocortical axonogenesis and adult tactile sensory behavior associated with maternal microbiome depletion. Metabolomic profiling reveals that the maternal microbiota regulates levels of numerous small molecules in the maternal serum as well as the brains of fetal offspring. Select microbiota-dependent metabolites – trimethylamine N-oxide, 5-aminovalerate, imidazole propionate, and hippurate – sufficiently promote axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with the metabolites during early gestation abrogates deficiencies in fetal thalamocortical axons and prevents abnormalities in tactile sensory behavior in offspring from microbiome-depleted dams. Altogether, these findings reveal that the maternal gut microbiome promotes fetal thalamocortical axonogenesis and select tactile sensory behaviors in mice, likely by signaling of microbially modulated metabolites to neurons in the developing brain.
2020-04-17 | GSE147183 | GEO
Project description:Myostatin (gene symbol: <i>Mstn</i>) is an autocrine and paracrine inhibitor of muscle growth. Pregnant mice with genetically reduced levels of myostatin give birth to offspring with greater adult muscle mass and bone biomechanical strength. However, maternal myostatin is not detectable in fetal circulations. Fetal growth is dependent on the maternal environment, and the provisioning of nutrients and growth factors by the placenta. Thus, this study examined the effect of reduced maternal myostatin on maternal and fetal serum metabolomes, as well as the placental metabolome. Fetal and maternal serum metabolomes were highly distinct, which is consistent with the role of the placenta in creating a specific fetal nutrient environment. There was no effect from myostatin on maternal glucose tolerance or fasting insulin. In comparisons between pregnant control and <i>Mstn</i><sup>+/-</sup> mice, there were more significantly different metabolite concentrations in fetal serum, at 50, than in the mother's serum at 33, confirming the effect of maternal myostatin reduction on the fetal metabolic milieu. Polyamines, lysophospholipids, fatty acid oxidation, and vitamin C, in fetal serum, were all affected by maternal myostatin reduction.
2023-06-08 | MTBLS3345 | MetaboLights
Project description:Purpose: Next generation bulk RNA sequencing of a large group (37 individuals) of matched tissues (fetal brain and fetal placenta) from human fetuses collected via elective termination at 72-82 days post conception (d.p.c.), a timeframe that closely matches the embryonic developmental window used in our mouse studies (14.5-16.5) Methods: Human placenta (maternal decidua separated from fetal placenta) and fetal brain tissues were obtained from the NIH-supported Laboratory of Developmental Biology at the University of Washington between the years 1999 and 2010 and used under a protocol approved by the Duke University Institutional Review Board (Pro00014066). Tissue specimens were stored at -80°C until required for RNA or protein extraction. Prior to collection, informed consent was obtained from all individuals undergoing the elective termination. RNA from human tissue was prepared for sequencing using an Illumina TrueSeq RNA Exome kit and sequenced on an Illumina NovaSeq 6000 configured for a S2 flow cell at 50bp PE. Results: PCR for the Y chromosome (SRY) identified 17 male and 20 female fetal tissue sets, with the average age of 78.2 d.p.c. for both sexes. No maternal data were available, so we assessed decidual triglyceride accumulation to use as a proxy for maternal weight, given that women with overweight/obesity exhibit triglyceride accumulation in the placenta. Triglyceride levels trended higher in pregnancies with female fetuses, but there was no significant difference between triglyceride accumulation in decidua associated with male or female pregnancies. Pearson's Correlation of gene expression with maternal triglyceride accumulation from bulk RNA-seq from 16 matched male and 19 matched female brain and placenta samples revealed a strong dimorphic trend in gene expression. In male pregnancies, differentially correlated genes were predominantly over-expressed with increasing maternal weight (i.e. gene expression increased as maternal triglycerides increased); the opposite effect was seen in female pregnancies. In the male brain, only 45 genes significantly correlated with maternal triglyceride accumulation (either positive or negative), whereas 781 genes were significantly correlated in females.
2021-11-18 | GSE188872 | GEO
Project description:Both the fetus and the mother who are involved in maternal anti-fetal rejection during pregnancy show distinct alterations in the peripheral blood transcriptome Total RNA isolated from umbilical cord blood and maternal blood was compared between cases without (Normal) and with maternal anti-fetal rejection (FIRS2) using whole genome DASL assay.
2012-03-31 | E-GEOD-28387 | biostudies-arrayexpress