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Tissue-specific and SRSF1-dependent splicing of fibronectin, a matrix protein that controls host cell invasion.

ABSTRACT: Cell invasion targets specific tissues in physiological placental implantation and pathological metastasis, which raises questions about how this process is controlled. We compare dermis and endometrium capacities to support trophoblast invasion, using matching sets of human primary fibroblasts in a coculture assay with human placental explants. Substituting endometrium, the natural trophoblast target, with dermis dramatically reduces trophoblast interstitial invasion. Our data reveal that endometrium expresses a higher rate of the fibronectin (FN) extra type III domain A+ (EDA+) splicing isoform, which displays stronger matrix incorporation capacity. We demonstrate that the high FN content of the endometrium matrix, and not specifically the EDA domain, supports trophoblast invasion by showing that forced incorporation of plasma FN (EDA-) promotes efficient trophoblast invasion. We further show that the serine/arginine-rich protein serine/arginine-rich splicing factor 1 (SRSF1) is more highly expressed in endometrium and, using RNA interference, that it is involved in the higher EDA exon inclusion rate in endometrium. Our data therefore show a mechanism by which tissues can be distinguished, for their capacity to support invasion, by their different rates of EDA inclusion, linked to their SRSF1 protein levels. In the broader context of cancer pathology, the results suggest that SRSF1 might play a central role not only in the tumor cells, but also in the surrounding stroma.

SUBMITTER: Lopez-Mejia IC

PROVIDER: S-EPMC3806663 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Tissue-specific and SRSF1-dependent splicing of fibronectin, a matrix protein that controls host cell invasion.

Lopez-Mejia Isabel Cristina IC De Toledo Marion M Della Seta Flavio F Fafet Patrick P Rebouissou Cosette C Deleuze Virginie V Blanchard Jean Marie JM Jorgensen Christian C Tazi Jamal J Vignais Marie-Luce ML

Molecular biology of the cell 20130821 20

Cell invasion targets specific tissues in physiological placental implantation and pathological metastasis, which raises questions about how this process is controlled. We compare dermis and endometrium capacities to support trophoblast invasion, using matching sets of human primary fibroblasts in a coculture assay with human placental explants. Substituting endometrium, the natural trophoblast target, with dermis dramatically reduces trophoblast interstitial invasion. Our data reveal that endom ...[more]

PMID: 23966470

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Project description:Systemic autoimmune diseases are characterized by hyperactive effector T cells (Teffs), aberrant cytokines and chemokines, and dysfunctional regulatory T cells (Tregs). We previously uncovered new roles for serine/arginine-rich splicing factor 1 (SRSF1) in the control of genes involved in T cell signaling and cytokine production in human T cells. SRSF1 levels are decreased in T cells from patients with systemic lupus erythematosus (SLE), and low levels correlate with severe disease. Moreover, T cell-conditional Srsf1-deficient mice recapitulate the autoimmune phenotype, exhibiting CD4 T cell hyperactivity, dysfunctional Tregs, systemic autoimmunity, and tissue inflammation. However, the role of SRSF1 in controlling molecular programs in Teffs and Tregs and how these pathways are implicated in autoimmunity is not known. Here, by comparative bioinformatics analysis, we demonstrate that SRSF1 controls largely distinct gene programs in Tregs and Teffs in vivo. SRSF1 regulates 189 differentially expressed genes (DEGs) unique to Tregs, 582 DEGs unique to Teffs, and 29 DEGs shared between both. Shared genes included IL-17A, IL-17F, CSF1, CXCL10, and CXCR4, and were highly enriched for inflammatory response and cytokine-cytokine receptor interaction pathways. SRSF1 controls distinct pathways in Tregs, which include chemokine signaling and immune cell differentiation, compared with pathways in Teffs, which include cytokine production, T cell homeostasis, and activation. We identified putative mRNA binding targets of SRSF1 which include CSF1, CXCL10, and IL-17F. Finally, comparisons with transcriptomics profiles from lupus-prone MRL/lpr mice reveal that SRSF1 controls genes and pathways implicated in autoimmune disease. The target genes of SRSF1 and putative binding targets we discovered, have known roles in systemic autoimmunity. Our findings suggest that SRSF1 controls distinct molecular pathways in Tregs and Teffs and aberrant SRSF1 levels may contribute to their dysfunction and immunopathogenesis of systemic autoimmune disease.

Dataset Information

Tissue-specific and SRSF1-dependent splicing of fibronectin, a matrix protein that controls host cell invasion.

Publications

Tissue-specific and SRSF1-dependent splicing of fibronectin, a matrix protein that controls host cell invasion.

Similar Datasets

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