Effect of SERT LOF on Drosophila Kenyon Cell subtypes postsynaptic to serotonin [scRNA-seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Drosophila melanogaster
PROVIDER: GSE227867 | GEO | 2023/06/26
REPOSITORIES: GEO
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Project description:to investigate the transcriptional effects on postsynaptic cells following SSRI-like SERT LOF, we used Drosophila mutants for SERT and compared to controls, isolating and profiling Kenyon Cells of the mushroom body
2023-06-26 | GSE227866 | GEO
Project description:Effect of SERT LOF on Drosophila Kenyon Cells postsynaptic to serotonin [bulkRNA-seq]
| PRJNA947203 | ENA
Project description:Effect of SERT LOF on Drosophila Kenyon Cell subtypes postsynaptic to serotonin [scRNA-seq]
| PRJNA947206 | ENA
Project description:Identifying new immune checkpoint molecules hindering antitumor T cell responses and devising new therapeutic blockades are key to the development of next-generation cancer immunotherapies. Here, we report the induction of the serotonin transporter (SERT) in solid tumor-infiltrating cytotoxic CD8 T cells, a molecule best known for its role in regulating serotonin neurotransmission in the brain. In solid tumors, CD8 T cells secrete serotonin, which stimulates their antitumor reactivities, while SERT functions as a negative regulator by depleting intratumoral serotonin. Inhibition of SERT using clinically approved selective serotonin reuptake inhibitors (SSRIs), a popular class of antidepressants, significantly suppressed tumor growth and enhanced CD8 T cell-mediated antitumor responses in various preclinical mouse syngeneic and human xenograft tumor models. Importantly, SSRI treatment exhibited significant therapeutic synergy with anti-PD-1 therapy, and clinical data correlation studies negatively associated intratumoral SERT expression with patient survival in a range of cancers. These findings highlight the significance of the intratumoral serotonin axis and identify SERT as a novel immune checkpoint, positioning SSRIs as promising candidates for next-generation combination cancer therapies.
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Project description:The serotonin transporter (SERT, SLC6A4), belonging to Na+ and Cl- dependent transporters, functions to regulate the availability of serotonin (5-HT) in various tissues including brain, platelets, and intestine. Alterations in 5-HT levels and/or SERT expression have been implicated in pathophysiological conditions including anxiety-like behavior, obesity, cardiovascular disorders and GI disorders such as IBD, IBS, and diarrhea. Accordingly, SERT deficiency in mice is pleiotropic with many different phenotypic traits. Transgenic mice with global deletion of SERT exhibit increased anxiety, abnormal GI motility, and obesity associated with hyperglycemia. Additionally, these mice are more susceptible to intestinal inflammation. The mechanism by which SERT deficiency underlies GI related disturbances and exacerbates the severity of gut inflammation is not known. Thus, we evaluated the ileal mRNA expression to identify potential intestinal targets that contribute to disease pathogenesis when the SERT gene is non-functional. For these studies, RNA was extracted from ileum mucosa from age matched (9-10 wk) control and SERT KO mice by Trizol and was subjected to Mouse mRNA and OneArray Profiling. Our microarray data revealed 492 significantly upregulated and 293 downregulated genes in SERT KO ileum. Pathway analysis revealed significant enrichment in cell cycle, signaling, chemotaxis, and epithelial transporters. Genes of interest were validated by RT-PCR, which included CYP1A1 (~20 fold decrease, p < 0.05), CLDN8 (~30% decrease, p < 0.05), and HMGCS2 (~7 fold increase, p < 0.05). Similar changes were found in colon. A remarkable decrease in expression of Cyp1a1, which encodes a cytochrome P450 enzyme, provides a novel role of serotonergic pathways in drug and xenobiotic detoxification. CLDN8 encodes for claudin 8, which is downregulated in patients with Crohn’s disease. Deficiency of HMGCS2, the mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase, is linked to hypoglycemia. Our data provides novel clues for differential expression of genes affected by 5-HT and/or SERT deficiency in the intestine.
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Project description:The brain can represent almost limitless objects to “categorize an unlabeled world”. This feat is supported by expansion layer circuit architectures, in which neurons carrying information about discrete sensory channels make combinatorial connections onto much larger postsynaptic populations. Combinatorial connections in expansion layers are modeled as randomized sets. The extent to which randomized wiring exists in vivo is debated, and how combinatorial connectivity patterns are generated during development is not understood. Non-deterministic wiring algorithms could program such connectivity using minimal genomic information. Here, we investigate anatomic and transcriptional patterns and perturb partner availability to ask how Kenyon cells, the expansion layer neurons of the insect mushroom body, obtain combinatorial input from olfactory projection neurons. Olfactory projection neurons form their presynaptic outputs in an orderly, predictable, and biased fashion. We find that Kenyon cells accept spatially co-located but molecularly heterogeneous inputs from this orderly map, and ask how Kenyon cell surface molecule expression impacts partner choice. Cell surface immunoglobulins are broadly depleted in Kenyon cells, and we propose that this allows them to form connections with molecularly heterogeneous partners. This model can explain how developmentally identical neurons acquire diverse wiring identities
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Project description:The brain can represent almost limitless objects to “categorize an unlabeled world” (Edelman, 1989). This feat is supported by expansion layer circuit architectures, in which neurons carrying information about discrete sensory channels make combinatorial connections onto much larger postsynaptic populations. Combinatorial connections in expansion layers are modeled as randomized sets. The extent to which randomized wiring existsin vivois debated, and how combinatorial connectivity patterns are generated during development is not understood. Non- deterministic wiring algorithms could program such connectivity using minimal genomic information. Here, we investigate anatomic and transcriptional patterns and perturb partner availability to ask how Kenyon cells, the expansion layer neurons of the insect mushroom body, obtain combinatorial input from olfactory projection neurons. Olfactory projection neurons form their presynaptic outputs in an orderly, predictable, and biased fashion. We find that Kenyon cells accept spatially co-located but molecularly heterogeneous inputs from this orderly map, and ask how Kenyon cell surface molecule expression impacts partner choice. Cell surface immunoglobulins are broadly depleted in Kenyon cells, and we propose that this allows them to form connections with molecularly heterogeneous partners. This model can explain how developmentally identical neurons acquire diverse wiring identities.
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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