1. Tissue-specific and SRSF1-dependent splicing of fibronectin, a matrix protein that controls host cell invasion
- Author
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Isabel C. Lopez-Mejia, Jamal Tazi, Jean Marie Blanchard, Virginie Deleuze, Marie-Luce Vignais, Flavio Della Seta, Marion de Toledo, Christian Jorgensen, Cosette Rebouissou, Patrick Fafet, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Université de Lausanne (UNIL), Cellules souches mésenchymateuses, environnement articulaire et immunothérapies de la polyarthrite rhumatoide, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR3, Université Montpellier 1 (UM1)-Université Montpellier 1 (UM1), Hôpital Lapeyronie [Montpellier] (CHU), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), Vignais, Marie-Luce, and Centre National de la Recherche Scientifique (CNRS)
- Subjects
MESH: Trophoblasts ,[SDV]Life Sciences [q-bio] ,Placenta ,Endometrium ,MESH: Serine-Arginine Splicing Factors ,Exon ,MESH: Pregnancy ,0302 clinical medicine ,Pregnancy ,MESH: Fibronectins ,MESH: Gene Expression Regulation, Developmental ,MESH: Placentation ,Nuclear protein ,MESH: Organ Specificity ,reproductive and urinary physiology ,0303 health sciences ,biology ,Serine-Arginine Splicing Factors ,MESH: Alternative Splicing ,Gene Expression Regulation, Developmental ,Nuclear Proteins ,RNA-Binding Proteins ,Articles ,MESH: Placenta ,female genital diseases and pregnancy complications ,Cell biology ,Trophoblasts ,[SDV] Life Sciences [q-bio] ,MESH: Endometrium ,medicine.anatomical_structure ,Cell Biology of Disease ,Organ Specificity ,030220 oncology & carcinogenesis ,RNA splicing ,embryonic structures ,MESH: Abortion, Induced ,Female ,medicine.medical_specialty ,Primary Cell Culture ,MESH: Primary Cell Culture ,03 medical and health sciences ,Splicing factor ,Internal medicine ,medicine ,Humans ,Neoplasm Invasiveness ,Molecular Biology ,030304 developmental biology ,MESH: Humans ,Alternative splicing ,Trophoblast ,Abortion, Induced ,MESH: Neoplasm Invasiveness ,Cell Biology ,Placentation ,Fibronectins ,Fibronectin ,Alternative Splicing ,MESH: RNA-Binding Proteins ,Endocrinology ,biology.protein ,MESH: Female ,MESH: Nuclear Proteins - Abstract
Matching sets of human primary fibroblasts cocultured with placenta explants are used to compare tissue capacities to support trophoblast invasion. Substituting endometrium with dermis dramatically reduces EVCT interstitial invasion, a phenomenon related to the ECM fibronectin content, FN alternative splicing, and expression of the SR protein SRSF1., 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.
- Published
- 2013