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  • 1.
    Biskou, Olga
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Jauregi-Miguel, Amaia
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi.
    Measuring intestinal permeability in celiac disease ex vivo, using Ussing chambers2023Ingår i: Celiac Disease / [ed] Ainara Castellanos-Rubio,Lorenzo Galluzzi, Academic Press , 2023, 1, Vol. 179, s. 21-38Kapitel i bok, del av antologi (Refereegranskat)
    Abstract [en]

    Multicellular organisms need epithelial barriers to remain compartmentalized and protected from external influences. Although much progress has been made in understanding barrier integrity disruption in Celiac disease (CD), the regulatory and genetic mechanisms underlying the increased intestinal epithelial flux are still unknown. As we learn more about the regulation of permeability in homeostasis and pathogenesis, we will be able to develop strategies to strengthen the epithelial barrier function in intestinal disorders, including CD. For this purpose, Ussing chambers are increasingly used in native tissue, such as gut mucosa or cell monolayers, to assess the integrity of the barrier. In particular, the Ussing chambers allow the measurement of paracellular and transcellular parameters of CD small intestinal biopsies under physiologically specific conditions. In diverse types of diseases, this method is commonly used to determine epithelial barrier defects, but its application to CD has not yet been widely expanded. To provide a great model of barrier ex vivo studies in CD, we facilitate a standard protocol to measure paracellular and transcellular permeability using the Ussing chamber.

  • 2.
    Söderholm, Simon
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Jauregi Miguel, Amaia
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Pagella, Pierfrancesco
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Ghezzi, Valeria
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Zambanini, Gianluca
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Nordin, Anna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Cantù, Claudio
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Single-cell response to Wnt signaling activation reveals uncoupling of Wnt target gene expression2023Ingår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 429, nr 2, artikel-id 113646Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Wnt signaling drives nuclear translocation of beta-catenin and its subsequent association with the DNA-bound TCF/LEF transcription factors, which dictate target gene specificity by recognizing Wnt responsive elements across the genome. beta-Catenin target genes are therefore thought to be collectively activated upon Wnt pathway stimulation. However, this appears in contrast with the non-overlapping patterns of Wnt target gene expression in several contexts, including early mammalian embryogenesis. Here we followed Wnt target gene expression in human embryonic stem cells after Wnt pathway stimulation at a single-cell resolution. Cells changed gene expression program over time consistent with three key developmental events: i) loss of pluripotency, ii) induction of Wnt target genes, and iii) mesoderm specification. Contrary to our expectation, not all cells displayed equal amplitude of Wnt target gene activation; rather, they distributed in a continuum from strong to weak responders when ranked based on the expression of the target AXIN2. Moreover, high AXIN2 did not always correspond to elevated expression of other Wnt targets, which were activated in different proportions in individual cells. The uncoupling of Wnt target gene expression was also identified in single cell transcriptomics profiling of other Wnt-responding cell types, including HEK293T, murine developing forelimbs, and human colorectal cancer. Our finding underlines the necessity to identify additional mechanisms that explain the heterogeneity of the Wnt/beta-catenin-mediated transcriptional outputs in single cells.

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  • 3.
    Pagella, Pierfrancesco
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Söderholm, Simon
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Nordin, Anna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Zambanini, Gianluca
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Ghezzi, Valeria
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Jauregi Miguel, Amaia
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Cantù, Claudio
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    The time-resolved genomic impact of Wnt/(3-catenin signaling2023Ingår i: CELL SYSTEMS, ISSN 2405-4712, Vol. 14, nr 7, s. 563-581.e7Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Wnt signaling orchestrates gene expression via its effector, (3-catenin. However, it is unknown whether (3-cat-enin binds its target genomic regions simultaneously and how this impacts chromatin dynamics to modulate cell behavior. Using a combination of time-resolved CUT & RUN against (3-catenin, ATAC-seq, and perturba-tion assays in different cell types, we show that Wnt/(3-catenin physical targets are tissue-specific, (3-catenin "moves"on different loci over time, and its association to DNA accompanies changing chromatin accessi-bility landscapes that determine cell behavior. In particular, Wnt/(3-catenin progressively shapes the chro-matin of human embryonic stem cells (hESCs) as they undergo mesodermal differentiation, a behavior that we define as "plastic."In HEK293T cells, on the other hand, Wnt/(3-catenin drives a transient chromatin open-ing, followed by re-establishment of the pre-stimulation state, a response that we define as "elastic."Future experiments shall assess whether other cell communication mechanisms, in addition to Wnt signaling, are ruled by time, cellular idiosyncrasies, and chromatin constraints. A record of this papers transparent peer review process is included in the supplemental information.

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  • 4.
    Jauregi Miguel, Amaia
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    The tight junction and the epithelial barrier in coeliac disease2021Ingår i: IMMUNOPATHOLOGY OF CELIAC DISEASE, Vol. 358, s. 105-132Artikel, forskningsöversikt (Refereegranskat)
    Abstract [en]

    Epithelial barriers are essential to maintain multicellular organisms well compartmentalized and protected from external environment. In the intestine, the epithelial layer orchestrates a dynamic balance between nutrient absorption and prevention of microorganisms, and antigen intrusion. Intestinal barrier function has been shown to be altered in coeliac disease but whether it contributes to the pathogenesis development or if it is merely a phenomenon secondary to the aberrant immune response is still unknown. The tight junction complexes are multiprotein cell-cell adhesions that seal the epithelial intercellular space and regulate the paracellular permeability of ions and solutes. These structures have a fundamental role in epithelial barrier integrity as well as in signaling mechanisms that control epithelial-cell polarization, the formation of apical domains and cellular processes such as cell proliferation, migration, differentiation, and survival. In coeliac disease, the molecular structures and function of tight junctions appear disrupted and are not completely recovered after treatment with gluten-free diet. Moreover, zonulin, the only known physiological regulator of the tight junction permeability, appears augmented in autoimmune conditions associated with TJ dysfunction, including coeliac disease. This chapter will examine recent discoveries about the molecular architecture of tight junctions and their functions. We will discuss how different factors contribute to tight junction disruption and intestinal barrier impairment in coeliac disease. To conclude, new insights into zonulin-driven disruption of tight junction structures and barrier integrity in coeliac disease are presented together with the advancements in novel therapy to treat the barrier defect seen in pathogenesis.

  • 5.
    Cambra, Josep M.
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Univ Murcia, Spain; Inst Biomed Res Murcia IMIB Arrixaca, Spain.
    Jauregi-Miguel, Amaia
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Alvarez-Rodriguez, Manuel
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Parrilla, Inmaculada
    Univ Murcia, Spain; Inst Biomed Res Murcia IMIB Arrixaca, Spain.
    Gil, Maria A.
    Univ Murcia, Spain; Inst Biomed Res Murcia IMIB Arrixaca, Spain.
    Martinez, Emilio A.
    Univ Murcia, Spain; Inst Biomed Res Murcia IMIB Arrixaca, Spain.
    Cuello, Cristina
    Univ Murcia, Spain; Inst Biomed Res Murcia IMIB Arrixaca, Spain.
    Rodriguez-Martinez, Heriberto
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Martinez Serrano, Cristina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Allogeneic Embryos Disregulate Leukemia Inhibitory Factor (LIF) and Its Receptor in the Porcine Endometrium During Implantation2020Ingår i: Frontiers in Veterinary Science, E-ISSN 2297-1769, Vol. 7, artikel-id 611598Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Despite its advantages for pig breeding, embryo transfer (ET) has a major handicap: high embryo mortality during the pre- and implantation period, probably caused by divergent phenomena of tolerance between the immunologically unrelated (i.e., allogeneic) embryos and the recipient sow. Thus, to reach a similar maternal tolerance as in conventional breeding by artificial insemination (AI) would be the key to ET-success. For this reason, we studied the expression of the leukemia inhibitory factor (LIF) cytokine and its receptor in the pig endometrium during the implantation period (days 18 and 24) in sows subjected to ET (AL group) vs. post-cervical-AI controls (Hemi-AL group). Quantification of expression was performed at both mRNA (rt-qPCR) and protein (WB) levels. The expression of endometrial LIF on day 24 was considerably lower in ET than in AI pregnancies. Correlations between endometrial mRNA levels of LIF and LIF-R showed that, contrary to early AI-pregnancies, ET-pregnancies lack an inverse relation between cytokine and receptor levels. In conclusion, ET-pregnancies lack sufficient endometrial levels of LIF to develop adequate immunotolerance mechanisms to prevent the rejection of allogeneic ET-embryos.

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  • 6.
    Gardela, Jaume
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Univ Autonoma Barcelona, Spain.
    Jauregi-Miguel, Amaia
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Martinez Serrano, Cristina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Rodriguez-Martinez, Heriberto
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Lopez-Bejar, Manel
    Univ Autonoma Barcelona, Spain; Western Univ Hlth Sci, CA 91766 USA.
    Alvarez-Rodriguez, Manuel
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Univ Autonoma Barcelona, Spain.
    Semen Modulates Inflammation and Angiogenesis in the Reproductive Tract of Female Rabbits2020Ingår i: Animals, E-ISSN 2076-2615, Vol. 10, nr 12, artikel-id 2207Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Simple Summary In mammals, the expression of regulatory genes is modified by the interaction between semen and the female reproductive tract. This study intends to unveil how mating or insemination with sperm-free seminal plasma, as well as the presence of preimplantation embryos, affects inflammation and angiogenesis in different segments of the reproductive tract of female rabbits. Gene expression of anti-inflammatory cytokines and angiogenesis mediators was analyzed in segmented tracts (cervix to infundibulum) in response to mating and sperm-free seminal plasma infusion. Moreover, the gene expression at different times post-mating was also analyzed. Results showed that gene expression changes were mainly localized in the uterus in the natural mating group, describing a clear temporal variation, while limited to the oviduct in the sperm-free seminal plasma group. These changes suggest an early response in the uterus and late modulation in the oviduct, distinctly demonstrating that semen and seminal plasma, through their interaction with the female reproductive tract, can differentially modulate the expression of anti-inflammatory and angiogenesis mediators. The maternal environment modulates immune responses to facilitate embryo development and ensure pregnancy. Unraveling this modulation could improve the livestock breeding systems. Here it is hypothesized that the exposure of the female rabbit reproductive tract to semen, as well as to early embryos, modulates inflammation and angiogenesis among different tissue segments. qPCR analysis of the gene expression changes of the anti-inflammatory interleukin-10 (IL10) and transforming growth factor beta family (TGF beta 1-3) and the angiogenesis mediator vascular endothelial growth factor (VEGF-A) were examined in response to mating or insemination with sperm-free seminal plasma (SP). Reproductive tract segment (cervix to infundibulum) samples were obtained in Experiment 1, 20 h after gonadotropin-releasing hormone (GnRH) stimulation (control), natural mating (NM) or vaginal infusion with sperm-free SP (SP-AI). Additionally, segmented samples were also obtained at 10, 24, 36, 68 or 72 h after GnRH-stimulation and natural mating (Experiment 2). The results of gene expression, analyzed by quantitative PCR, showed that NM effects were mainly localized in the uterine tissues, depicting clear temporal variation, while SP-AI effects were restricted to the oviduct. Changes in anti-inflammatory and angiogenesis mediators indicate an early response in the uterus and a late modulation in the oviduct either induced by semen or preimplantation embryos. This knowledge could be used in the implementation of physiological strategies in breeding systems to face the new challenges on rabbit productivity and sustainability.

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  • 7.
    Gardela, Jaume
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Universitat Autònoma de Barcelona, Bellaterra, Spain.
    Jauregi-Miguel, Amaia
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Martinez, Cristina A.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Rodriguez-Martinez, Heriberto
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Lopez-Bejar, Manel
    Universitat Autònoma de Barcelona, Bellaterra, Spain: Western University of Health Sciences, Pomona, CA, USA.
    Alvarez-Rodriguez, Manuel
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Universitat Autònoma de Barcelona, Bellaterra, Spain.
    Semen Modulates the Expression of NGF, ABHD2, VCAN, and CTEN in the Reproductive Tract of Female Rabbits2020Ingår i: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 11, nr 7, artikel-id E758Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Semen changes the gene expression in endometrial and oviductal tissues modulating important processes for reproduction. We tested the hypothesis that mating and/or sperm-free seminal plasma deposition in the reproductive tract affect the expression of genes associated with sperm-lining epithelium interactions, ovulation, and pre-implantation effects (nerve growth factor, NGF; α/β hydrolase domain-containing protein 2, ABHD2; C-terminal tensin-like protein, CTEN or TNS4; and versican, VCAN) in the period 10-72 h post-mating. In Experiment 1, does (n = 9) were treated with gonadotropin-releasing hormone (GnRH) (control), GnRH-stimulated, and vaginally infused with sperm-free seminal plasma (SP-AI), or GnRH-stimulated and naturally mated (NM). In Experiment 2, does (n = 15) were GnRH-stimulated and naturally mated. Samples were retrieved from the internal reproductive tracts (cervix-to-infundibulum) 20 h post-treatment (Experiment 1) or sequentially collected at 10, 24, 36, 68, or 72 h post-mating (Experiment 2, 3 does/period). All samples were processed for gene expression analysis by quantitative PCR. Data showed an upregulation of endometrial CTEN and NGF by NM, but not by SP-AI. The findings suggest that the NGF gene affects the reproductive tract of the doe during ovulation and beyond, influencing the maternal environment during early embryonic development.

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  • 8.
    Ruiz-Conca, Mateo
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Univ Autonoma Barcelona, Spain.
    Gardela, Jaume
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Univ Autonoma Barcelona, Spain.
    Jauregi-Miguel, Amaia
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Martinez Serrano, Cristina
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Rodriguez-Martinez, Heriberto
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten.
    Lopez-Bejar, Manel
    Univ Autonoma Barcelona, Spain; Western Univ Hlth Sci, CA 91766 USA.
    Alvarez-Rodriguez, Manuel
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Univ Autonoma Barcelona, Spain.
    Seminal Plasma Triggers the Differential Expression of the Glucocorticoid Receptor (NR3C1/GR) in the Rabbit Reproductive Tract2020Ingår i: Animals, E-ISSN 2076-2615, Vol. 10, nr 11, artikel-id 2158Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Simple Summary Glucocorticoids are steroid hormones modulating different functions in mammals, including reproduction, that act through the glucocorticoid receptor, encoded by the gene called NR3C1. Here, we describe how the expression levels of the glucocorticoid receptor change along the different compartments of the female rabbit internal reproductive tract 20 h after insemination with sperm-free seminal plasma or natural mating (whole semen) (Experiment 1) and how these levels change at 10, 24, 36, 68, and 72 h post-mating, during specific stages over time, i.e., ovulation, fertilization and the interval of early embryo development to the morula stage occurs (Experiment 2). NR3C1-upregulation was found in the infundibulum at 20 h after all treatments, especially after sperm-free seminal plasma infusion compared to mating (Experiment 1). In Experiment 2, the receptor gene expression levels increased in a spatio-temporal sequence, corresponding to the assumed location of the rabbit embryos (particularly morulae) in the oviductal various segments and timepoints (particularly 72 h), compared to down-expression at uterine regions. We conclude that NR3C1 may play a relevant role in the rabbit female reproductive tract. Rabbits are interesting as research animal models for reproduction, due to their condition of species of induced ovulation, with the release of endogenous gonadotropin-releasing hormone (GnRH) due to coitus. Glucocorticoid (GC) signaling, crucial for physiological homeostasis, is mediated through a yet unclear mechanism, by the GC receptor (NR3C1/GR). After mating, the female reproductive tract undergoes dynamic modifications, triggered by gene transcription, a pre-amble for fertilization and pregnancy. This study tested the hypothesis that when ovulation is induced, the expression of NR3C1 is influenced by sperm-free seminal plasma (SP), similarly to after mating (whole semen), along the different segments of the internal reproductive tract of female rabbits. Semen (mating) was compared to vaginal infusion of sperm-free SP (Experiment 1), and changes over time were also evaluated, i.e., 10, 24, 36, 68, and 72 h post-mating, corresponding to specific stages, i.e., ovulation, fertilization, and the interval of early embryo development up to the morula stage (Experiment 2). All does were treated with GnRH to induce ovulation. Samples were retrieved from seven segments of the reproductive tract (from the cervix to infundibulum), at 20 h post-mating or sperm-free SP infusion (Experiment 1) or at 10, 24, 36, 68, and 72 h post-mating (Experiment 2). Gene expression of NR3C1 was analyzed by qPCR. Results showed an increase in NR3C1 expression in the infundibulum compared to the other anatomical regions in the absence of spermatozoa when sperm-free SP infusion was performed (Experiment 1). Moreover, during the embryo transport through the oviduct, the distal isthmus was time-course upregulated, especially at 72 h, when morulae are retained in this anatomical region, while it was downregulated in the distal uterus at 68 h (Experiment 2). The overall results suggest that NR3C1, the GC receptor gene, assessed in the reproductive tract of does for the first time, shows differential expression changes during the interval of oviductal and uterine embryo transport that may imply a relevant role of the GC action, not only close to the site of ovulation and fertilization, but also in the endometrium.

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  • 9.
    Zimmerli, Dario
    et al.
    Univ Zurich, Switzerland; Netherlands Canc Inst, Netherlands.
    Borrelli, Costanza
    Swiss Fed Inst Technol, Switzerland.
    Jauregi Miguel, Amaia
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Söderholm, Simon
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    Brutsch, Salome
    Univ Zurich, Switzerland.
    Doumpas, Nikolaos
    Univ Zurich, Switzerland.
    Reichmuth, Jan
    Univ Zurich, Switzerland.
    Murphy-Seiler, Fabienne
    Ecole Polytech Fed Lausanne EPFL, Switzerland.
    Aguet, Michel
    Ecole Polytech Fed Lausanne EPFL, Switzerland.
    Basler, Konrad
    Univ Zurich, Switzerland.
    Moor, Andreas E.
    Swiss Fed Inst Technol, Switzerland.
    Cantù, Claudio
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för molekylär medicin och virologi. Linköpings universitet, Medicinska fakulteten.
    TBX3 acts as tissue-specific component of the Wnt/beta-catenin transcriptional complex2020Ingår i: eLIFE, E-ISSN 2050-084X, Vol. 9, artikel-id e58123Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BCL9 and PYGO are beta-catenin cofactors that enhance the transcription of Wnt target genes. They have been proposed as therapeutic targets to diminish Wnt signaling output in intestinal malignancies. Here we find that, in colorectal cancer cells and in developing mouse forelimbs, BCL9 proteins sustain the action of beta-catenin in a largely PYGO-independent manner. Our genetic analyses implied that BCL9 necessitates other interaction partners in mediating its transcriptional output. We identified the transcription factor TBX3 as a candidate tissue-specific member of the beta-catenin transcriptional complex. In developing forelimbs, both TBX3 and BCL9 occupy a large number of Wnt-responsive regulatory elements, genome-wide. Moreover, mutations in Bcl9 affect the expression of TBX3 targets in vivo, and modulation of TBX3 abundance impacts on Wnt target genes transcription in a beta-catenin- and TCF/LEF-dependent manner. Finally, TBX3 overexpression exacerbates the metastatic potential of Wnt-dependent human colorectal cancer cells. Our work implicates TBX3 as context-dependent component of the Wnt/beta-catenin-dependent transcriptional complex.

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