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Transcription Factor TLX1 Controls Retinoic Acid Signaling to Ensure Spleen Development [Microarray Expression]

ABSTRACT: The molecular mechanisms underlying asplenia, a condition often associated with overwhelming infections remain largely unknown. During spleen development, the transcription factor TLX1 controls morphogenesis and organ expansion, and loss of it causes spleen agenesis. However, the downstream signaling pathways that are deregulated in the absence of TLX1 are mostly unknown. Herein, we demonstrate that loss of Tlx1 in the splenic mesenchyme causes increased retinoic acid (RA) signaling. Increased RA activity causes premature differentiation of the splenic mesenchyme and reduced vasculogenesis of the splenic anlage. Moreover, excess or deficiency in RA signaling, as observed in Cyp26b1 or Rdh10 mutants respectively, also results in spleen growth arrest. Genome-wide analysis revealed that TLX1 binds RA-associated genes through the AP-1 site and cooperates with the AP-1 family transcription factors to regulate transcription. Pharmacological inhibition of RA signaling partially rescues the spleen defect. These findings establish the critical role of TLX1 in controlling RA metabolism, and provide novel mechanistic insights into the molecular determinants underlying congenital asplenia. Samples: 3 replicates of E13.5 spleens from Tlx1 heterozygous embryos were compared to 3 replicates of E13.5 spleens from Tlx1 homozygous embryos

ORGANISM(S): Mus musculus

SUBMITTER: Andrea Brendolan

PROVIDER: E-GEOD-68519 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Transcription Factor TLX1 Controls Retinoic Acid Signaling to Ensure Spleen Development [Microarray Expression]

Project description:The molecular mechanisms underlying asplenia, a condition often associated with overwhelming infections remain largely unknown. During spleen development, the transcription factor TLX1 controls morphogenesis and organ expansion, and loss of it causes spleen agenesis. However, the downstream signaling pathways that are deregulated in the absence of TLX1 are mostly unknown. Herein, we demonstrate that loss of Tlx1 in the splenic mesenchyme causes increased retinoic acid (RA) signaling. Increased RA activity causes premature differentiation of the splenic mesenchyme and reduced vasculogenesis of the splenic anlage. Moreover, excess or deficiency in RA signaling, as observed in Cyp26b1 or Rdh10 mutants respectively, also results in spleen growth arrest. Genome-wide analysis revealed that TLX1 binds RA-associated genes through the AP-1 site and cooperates with the AP-1 family transcription factors to regulate transcription. Pharmacological inhibition of RA signaling partially rescues the spleen defect. These findings establish the critical role of TLX1 in controlling RA metabolism, and provide novel mechanistic insights into the molecular determinants underlying congenital asplenia.

2016-07-01 | GSE68519 | GEO

Transcription Factor TLX1 Controls Retinoic Acid Signaling to Ensure Spleen Development [ChIP-Seq]

Project description:The molecular mechanisms that underlie spleen development and congenital asplenia, a condition linked to increased risk of overwhelming infections, remain largely unknown. The transcription factor TLX1 controls cell fate specification and organ expansion during spleen development, and Tlx1 deletion causes asplenia in mice. Deregulation of TLX1 expression has recently been proposed in the pathogenesis of congenital asplenia in patients carrying mutations of the gene-encoding transcription factor SF-1. Herein, we have shown that TLX1-dependent regulation of retinoic acid (RA) metabolism is critical for spleen organogenesis. In a murine model, loss of Tlx1 during formation of the splenic anlage increased RA signaling by regulating several genes involved in RA metabolism. Uncontrolled RA activity resulted in premature differentiation of mesenchymal cells and reduced vasculogenesis of the splenic primordium. Pharmacological inhibition of RA signaling in Tlx1-deficient animals partially rescued the spleen defect. Finally, spleen growth was impaired in mice lacking either cytochrome 26B1 (Cyp26b1), which results in excess RA, or retinol dehydrogenase 10 (Rdh10), which results in RA deficiency. Together, these findings establish TLX1 as a critical regulator of RA metabolism and provide mechanistic insight into the molecular determinants of human congenital asplenia.

2016-07-01 | GSE81660 | GEO

Transcription Factor TLX1 Controls Retinoic Acid Signaling to Ensure Spleen Development [ChIP-Seq]

2016-07-01 | E-GEOD-81660 | biostudies-arrayexpress

Gene expression profiles of primary LN3 T-ALL cells and wild-type T-lineage cells from the thymus and spleen

Project description:T cell acute lymphoblastic leukemia (T-ALL) develops spontaneously in the thymus of LN3 mice and infiltrates secondary organs, including spleen. We found leukemia-associated myeloid cells from the spleens of overtly sick LN3 mice significantly support survival of splenic T-ALL cells, but not tumor-free splenic CD8+ T cells, in vitro. To determine gene signatures induced in T-ALL cells by tumor-supportive myeloid cells, but not induced in wild-type T cells, we transcriptionally profiled primary LN3 T-ALL cells from leukemic mice and T-lineage cells from tumor-free mice, isolated from thymuses and spleens, via RNA-sequencing.

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Aging-triggered iron-rich insoluble protein aggregates in the spleen originate chiefly from red pulp macrophages.

Project description:Both iron homeostasis and erythropoiesis are known to be affected by aging. Iron needs in mammals are met primarily by iron recycling from senescent red blood cells (RBCs), a task chiefly accomplished by red pulp macrophages (RPMs) in the spleen. Given that RPMs continuously process iron, their cellular functions might be susceptible to age-dependent decline, a possibility that has been unexplored to date. In our project, we identified a formation of undegradable iron- and heme-rich extracellular aggregates in the spleens of 10-11-month-old female mice. To better understand the origin of these aggregates, here, we performed: i) protein identification and intrasample quantification (iBAQ) of proteins of magnetically-isolated red pulp macrophages from spleens of two female 8-weeks-old C57BL/6J (maintained on a standard diet) and ii) label-free quantification of proteins of the splenic protein aggregates formed in the mouse spleen 24 hours after intraperitoneal iron dextran injection, using dextran-injected mice as a control. Two 8-week-old C57BL/6J mice per group were analyzed. This dataset is related to the project PXD032900, which describes quanytitative analysis of proteins in aggregates magnetically isolated from spleen of aged (standard or iron-reduced diet) and young mice (standard diet).

2023-02-02 | PXD038660 | Pride

Gene expression of human splenic littoral cells compared with splenic vascular endothelial cells

Project description:Splenic littoral cells (SLCs) are specialized endothelial cells (ECs) lining the sinusoids of the human spleen and function as the filters and scavengers for senescent or altered red blood cells. In this study we isolated SLCs and vascular ECs from normal human spleens using immunostaining and flow cytometric sorting. We used microarrays to analyze the underling mechanism of SLC’s unique functions that distinguish themm from splenic vascular ECs and identified sets of differentially expressed genes

2017-12-08 | GSE92368 | GEO

A comparison of microRNA expression profiles from splenic hemangiosarcoma, splenic nodular hyperplasia, and normal spleens of dogs

Project description:Splenic masses are common in older dogs and may be malignant, benign, or non-neoplastic; yet diagnosis preceding splenectomy and histopathology remains elusive. MicroRNAs (miRNAs) are 18-25 nucleotide, single stranded, non-coding RNAs that play a role in post-transcriptional regulation. MicroRNAs in tumor samples have been used to diagnose tumors, provide prognostic information, and aid in targeted treatments in human medicine, but have not been extensively evaluated in veterinary medicine. The objective of this study was to determine differential expression of microRNAs (miRNAs) between canine splenic hemangiosarcoma, canine splenic nodular hyperplasia, and normal canine spleens by use of RNA-sequencing. Eighteen miRNAs were found to be significantly differentially expressed between hemangiosarcoma and nodular hyperplasia only. The five of these with the largest fold change were mir-193a, mir-450a, mir-503, mir-542, and mir-876. Four miRNA were significantly differentially expressed between hemangiosarcoma and nodular hyperplasia and also hemangiosarcoma and normal spleen (mir-126, mir-150, mir-203, and mir-452). Findings of this study show that miRNA expression profiles are different between canine splenic hemangiosarcoma, nodular hyperplasia, and normal spleens. This is a preliminary study with findings of clinical relevance, as masses of the spleen cannot be diagnosed pre-operatively in most cases. Canine splenic masses are relatively common, and validation these findings is warranted for potential use as a diagnostic test.

2016-09-29 | GSE81113 | GEO

Exploring the molecular mechanism of dihydroartemisinin regulating spleen immunity based on proteomics and phosphoproteomic

Project description:The molecular mechanisms through which dihydroartemisinin (DHA) induces immunomodulation in vivo remain unclear. Herein, DHA-regulated proteins and their phosphorylation profiles were identified and characterized, in the spleens of mice, using proteomics and phosphoproteomic approaches. We found that DHA upregulates proliferation-associated protein (cyclin-dependent kinases, Ki67, and mini-chromosome maintenance and proliferating cell nuclear antigen) expression via modulation of mitogen-activated protein kinase (MAPK) - activator protein 1 (AP-1) signaling pathway activity. In addition, DHA promoted the proliferation of CD4 T naïve, proliferated CD25+CD4+ T-cells, and BrdU+ interferon (IFN)-γ-producing CD8+ T cells. These predicted mechanisms of action were then validated in a Plasmodium berghei ANKA-infected mouse model of malaria and a cyclophosphamide-induced immunosuppression model. Collectively, the findings of this study, for the first time, provide robust evidence that DHA induced the expansion of the splenic T-cell pool through MAPK-AP1 signaling. The data provided in-depth knowledge in the mechanism of DHA-mediated immunomodulation.

2022-05-29 | PXD030353 | Pride

Transcription Factor TLX1 Controls Retinoic Acid Signaling to Ensure Spleen Development

Project description:Transcription Factor TLX1 Controls Retinoic Acid Signaling to Ensure Spleen Development

| PRJNA322247 | ENA

Whole spleen transcriptome during acute phase of infection in an avirulent Plasmodium chabaudi chabaudi AS infection.

Project description:The spleen is considered as the major lymphoid organ involved in generating immune responses to the erythrocytic stages of the malaria parasite, Plasmodium, but access to human spleens is not practical and most studies rely on peripheral blood for assessing immune responses. However, the suitability of peripheral blood as a proxy for splenic immune responses is unknown. Here, we have analysed transcriptome activity for whole spleens over 12 days of erythrocytic stage Plasmodium chabaudi infection in C57BL/6 mice. These data will be compared with comparable data taken from whole blood: and previously published: GSE93631

2019-11-19 | GSE123391 | GEO

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