The serotonin transporter is a regulator of neurodegeneration and axon regeneration after retinal injury
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ABSTRACT:
PROVIDER: PRJNA644185 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12147706_1.fastq.gz | Fastqsanger.gz | |||
| SRR12147706_2.fastq.gz | Fastqsanger.gz | |||
| SRR12147707_1.fastq.gz | Fastqsanger.gz | |||
| SRR12147707_2.fastq.gz | Fastqsanger.gz | |||
| SRR12147708_1.fastq.gz | Fastqsanger.gz |
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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: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: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:Serotonin transporter-dependent histone serotonylation in placenta contributes to the neurodevelopmental transcriptome
| PRJNA1033596 | ENA
Project description:Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed drugs to pregnant women experiencing depression. While such drugs might be beneficial in combating depression by competitively binding to serotonin transporter (SERT), they can adversely affect the placenta and fetal brain development. Parietal trophoblast giant cells (pTGCs) in the mouse placenta are postulated to internalize maternal serotonin (5-HT) via transport through SERT, encoded by Slc6a4. The placenta provides the initial source of 5-HT to the emerging brain via the placental-brain axis. Disruption of 5-HT acquisition by pTGCs due to genetic deletion of Slc6a4 is hypothesized to impact placental and fetal brain development. A transgenic mouse line with the SERT transporter selectively deleted was created by pairing mice with Cre-recombinase linked to proliferin (Prl2c2) with LoxP sites flanking the Slc6a4 gene. Proliferin is solely expressed by pTGCs and other giant cells of the placenta. To compare placental and fetal brain development in selective Sl6a4 KO and WT mice, 5-HT content in the placenta and fetal brains of the mice was measured. No significant differences in 5-HT content were evident between knockout (KO) and wild-type (WT) placenta and fetal brain. However, there was significantly lower average number of pTGCs in KO placentas compared to WT (p ≤ 0.05). Sexually dimorphic differences in gene expression were evident in the placenta and fetal brain between KO and WT counterparts with female conceptuses showing the most dramatic responses. Findings suggest that ablation of SERT in pTGC disrupts the placenta-brain axis in a sex-dependent manner. These results might have important clinical ramifications for pregnant women being treated with SSRIs.
2025-08-02 | GSE304347 | 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 | 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:IGF-I exert multiple effects in different retinal cell populations in both physiological and pathological conditions. Transgenic mice overexpressing IGF-I in the retina showed impaired electroretinographic responses at 6-7 months of age that worsen with age. This retinal neuronal dysfunction was correlated with the loss of rod photoreceptors, bipolar, ganglion and amacrines cells. Neuronal alterations were preceded by the overexpression of retinal stress markers, acute phase proteins and gliosis-related genes. IGF-I overexpression leads to chronic gliosis and microgliosis in TgIGF-I retinas, with mild oxidative stress, impaired recycling of glutamate and defective potassium buffering. These impaired supportive functions can contribute to neurodegeneration in TgIGF-I retinas, together with the increased production of pro-inflammatory cytokines, potential mediators of neuronal death.
2013-08-01 | E-MEXP-3786 | biostudies-arrayexpress
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