Gene Expression and Histopathological Changes in the Placenta of the Serotonin Transporter (Slc6a4) Knockout Mouse Suggest a Role for Serotonin in Controlling Nutrient Acquisition
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ABSTRACT:
PROVIDER: PRJNA732506 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| SRR14639021_1.fastq.gz | Fastqsanger.gz | |||
| SRR14639021_2.fastq.gz | Fastqsanger.gz | |||
| SRR14639022_1.fastq.gz | Fastqsanger.gz | |||
| SRR14639022_2.fastq.gz | Fastqsanger.gz | |||
| SRR14639023_1.fastq.gz | Fastqsanger.gz |
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Project description:We report the application of single-molecule-based sequencing technology for high-throughput profiling in 5-HT transporter SLC6A4 gene knockout 12.5 dpc mouse placenta. This study was to test the hypothesis that ablation of the Slc6a4 gene would result in morphological changes correlated with defined gene expression changes in the placenta. We found that Slc6a4 KO placentas had a much increased pTGC to spongiotrophoblast area ratio relative to WT placentas. Slc6a4 KO placentas had significantly elevated expression of genes associated with intestinal functions such as nutrient sensing, uptake, and catabolism, and blood clotting. Integrative correlation analyses revealed that upregulation of many of these genes was correlated with the expansion of the pTGC layer. One other key gene in this module was dopa decarboxylase (Ddc), which catalyzes the conversion of L-5-hydroxytryptophan to 5-HT. Our studies suggest a new paradigm relating to how 5-HT operates in the placenta, namely as a factor regulating metabolic functions and blood clotting through autocrine actions. We further suggest that the pTGC are functional analogs of the enterochromaffin 5-HT-positive cells of the gut, which have roles in controlling similar activities within the intestinal mucosa. Our studies suggest a new paradigm in thinking about how 5-HT acts in the placenta, namely not so much as a classic neurotransmitter but as an endocrine factor regulating metabolic functions and blood clotting through autocrine actions.
2021-10-04 | GSE175489 | GEO
Project description:IntroductionThe mouse placenta accumulates and possibly produces serotonin (5-hydroxytryptamine; 5-HT) in parietal trophoblast giant cells (pTGC) located at the interface between the placenta and maternal deciduum. However, the roles of 5-HT in placental function are unclear. This lack of information is unfortunate, given that selective serotonin-reuptake inhibitors are commonly used to combat depression in pregnant women. The high affinity 5-HT transporter SLC6A4 (also known as SERT) is the target of such drugs and likely controls much of 5-HT uptake into pTGC and other placental cells. We hypothesized that ablation of the Slc6a4 gene would result in morphological changes correlated with placental gene expression changes, especially for those involved in nutrient acquisition and metabolism, and thereby, provide insights into 5-HT placental function.MethodsPlacentas were collected at embryonic age (E) 12.5 from Slc6a4 knockout (KO) and wild-type (WT) conceptuses. Histological analyses, RNAseq, qPCR, and integrative correlation analyses were performed.ResultsSlc6a4 KO placentas had a considerable increased pTGC to spongiotrophoblast area ratio relative to WT placentas and significantly elevated expression of genes associated with intestinal functions, including nutrient sensing, uptake, and catabolism, and blood clotting. Integrative correlation analyses revealed upregulation of many of these genes was correlated with pTGC layer expansion. One other key gene was dopa decarboxylase (Ddc), which catalyzes conversion of L-5-hydroxytryptophan to 5-HT.DiscussionOur studies possibly suggest a new paradigm relating to how 5-HT operates in the placenta, namely as a factor regulating metabolic functions and blood coagulation. We further suggest that pTGC might be functional analogs of enterochromaffin 5-HT-positive cells of the intestinal mucosa, which regulate similar activities within the gut. Further work, including proteomics and metabolomic studies, are needed to buttress our hypothesis.
| S-EPMC8585720 | biostudies-literature
Project description:The serotonin (5-HT) transporter (SERT) is a key determinant of the concentration of 5-HT available for synaptic signaling and is the target of the antidepressant-selective 5-HT reuptake inhibitors (SSRIs). In addition to the role of SERT in mediating the actions of antidepressant medications, multiple, rare gain of function coding variants in SERT have been identified in subjects with autism spectrum disorder (ASD). The Blakely lab has extensively characterized the structural and functional impact of one of these variants, SERT Ala56, in vitro and in vivo, revealing a constitutively-imposed, biased conformation that enhances transporter function and that perturbs transporter regulation. We hypothesize that SERT Ala56 disrupts the interactions of molecular networks that normally ensure proper transporter structure, localization and regulation, and whose elucidation may reveal new determinants of serotonergic dysfunction in ASD. Here, we pursue an unbiased proteomic analysis of changes in SERT interacting protein (SIPs) imposed by the SERT Ala56 variant, expressed in transgenic mice. Further investigation of the SIPs and associated networks nominated through our studies may provide new opportunities to detect and modulate brain networks that contribute to the underlying complexity of ASD.
2020-05-29 | PXD018695 | Pride
Project description:Loss of specialized neurons in neurodegenerative diseases and after nerve injury is mediated in a neuronal subtype- and region-specific fashion. However, little is known about what molecular contexts define selective vulnerability. Here, we demonstrate that retinal ganglion cells (RGCs) in the mouse peripheral ventrotemporal (VT) retina are the most susceptible to optic nerve injury. Mechanistically, we show that the ventral-specific molecule, the serotonin transporter (SERT) is upregulated on VT axons within one day after injury and loss of SERT attenuates VT RGC death and promotes axon regeneration. From RNA-seq analysis, the transmembrane protein Gpnmb has been identified as a target downregulated by SERT. Moreover, GPNMB is involved in RGC protection and axon regeneration. Together, our studies reveal the serotonin transporter as a determinant of selective vulnerability.
2020-07-11 | GSE153812 | GEO
Project description:To unravel the effect of increased extracellular serotonin levels on brain development, RNA-seq was performed in the medial prefrontal cortex of serotonin transporter knockout and wildtype rats at five time points from early life to adulthood (postnatal day (PND) 8, 14, 21, 35 and 70). Differential expression of protein-coding genes was analyzed and we demonstrate that a lack of functional 5-HTT especially affects gene expression in early postnatal life (PND8).
2020-10-01 | GSE79909 | GEO
Project description:The serotonin transporter (SERT), a member of the neurotransmitter:sodium symporter family, is responsible for termination of serotonergic signaling by re-uptake of serotonin (5-HT) into the presynaptic neuron. Its key role in synaptic transmission makes it a major drug target, e.g. for the treatment of depression, anxiety and post-traumatic stress. Here, we apply hydrogen-deuterium exchange mass spectrometry to probe the conformational dynamics of human SERT in the absence and presence of known substrates and targeted drugs. Our results reveal significant changes in dynamics in regions TM1, EL3, EL4, and TM12 upon binding co-transported ions (Na+/K+) and ligand-mediated changes in TM1, EL3 and EL4 upon binding 5-HT, the drugs S-citalopram, cocaine and ibogaine. Our results provide a comprehensive direct view of the conformational response of SERT upon binding both biologically relevant substrate/ions and ligands of pharmaceutical interest, thus advancing our understanding of the structure-function relationship in SERT.
2019-05-15 | PXD013750 | Pride
Project description:Brain development requires appropriate regulation of serotonin (5-HT) signaling from distinct tissue sources across embryogenesis. At the maternal-fetal interface, the placenta is thought to be an important contributor of offspring brain 5-HT and is critical to overall fetal health. Yet, how placental 5-HT is acquired, and the mechanisms through which 5-HT influences placental functions, are not well understood. Recently, our group identified a novel epigenetic role for 5-HT, in which 5-HT can be added to histone proteins to regulate transcription, a process called H3 serotonylation. Here, we show that H3 serotonylation undergoes dynamic regulation during placental development, corresponding to gene expression changes that are known to influence key metabolic processes. Using transgenic mice, we demonstrate that placental H3 serotonylation largely depends on 5-HT uptake by the serotonin transporter (Sert/Slc6a4). Sert deletion robustly reduces enrichment of H3 serotonylation across the placental genome, and disrupts neurodevelopmental gene networks in offspring brain tissues. Thus, these findings suggest a novel role for H3 serotonylation in coordinating placental transcription at the intersection of maternal physiology and offspring brain development.
2024-01-23 | GSE246539 | GEO
Project description:Brain development requires appropriate regulation of serotonin (5-HT) signaling from distinct tissue sources across embryogenesis. At the maternal-fetal interface, the placenta is thought to be an important contributor of offspring brain 5-HT and is critical to overall fetal health. Yet, how placental 5-HT is acquired, and the mechanisms through which 5-HT influences placental functions, are not well understood. Recently, our group identified a novel epigenetic role for 5-HT, in which 5-HT can be added to histone proteins to regulate transcription, a process called H3 serotonylation. Here, we show that H3 serotonylation undergoes dynamic regulation during placental development, corresponding to gene expression changes that are known to influence key metabolic processes. Using transgenic mice, we demonstrate that placental H3 serotonylation largely depends on 5-HT uptake by the serotonin transporter (Sert/Slc6a4). Sert deletion robustly reduces enrichment of H3 serotonylation across the placental genome, and disrupts neurodevelopmental gene networks in offspring brain tissues. Thus, these findings suggest a novel role for H3 serotonylation in coordinating placental transcription at the intersection of maternal physiology and offspring brain development.
2024-01-23 | GSE246538 | GEO
Project description:Serotonin transporter-dependent histone serotonylation in placenta contributes to the neurodevelopmental transcriptome
| PRJNA1033596 | ENA
Project description:The amygdala is a prominent region of the brain processing stress-related emotion and vigilance. Additionally it is known that the serotonergic system is strongly involved in stress response and adaptation. The serotonin transporter (5-HTT) as key regulator of serotonergic activity in the brain is associated with stress-related neuropsychiatric disorders as well as heightened trait anxiety/dysphoria and exaggerated response to fear and environmental stress in humans. Also 5-HTT knockout mice display increased anxiety- and depression-related behaviors, altered stress reactivity and stress-coping abilities, gene expression differences and altered dendritic morphology. We measured immediate reactions to an acute stressor in 5-HTT knockout mice vs. wildtypes using microarrays for genome wide gene expression profiling in the amygdala and identified different functional clusters dependent on condition and genotype. Global amygdalar gene expression profiles were compared between 5-HTT knockout vs. wildtype mice in the conditions control vs. acute stressor in a total sample of 20 (5 biological replicates per genotype and condition).
2013-03-13 | E-GEOD-40393 | biostudies-arrayexpress