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Thomas Gridley - One of the best experts on this subject based on the ideXlab platform.
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SNAI1 regulates cell lineage allocation and stem cell maintenance in the mouse intestinal epithelium
The EMBO Journal, 2015Co-Authors: Katja Horvay, Thierry Jarde, Franca Casagranda, Victoria M Perreau, Katharina Haigh, Christian M Nefzger, Reyhan Akhtar, Thomas Gridley, Geert BerxAbstract:Snail family members regulate epithelial-to-mesenchymal transition (EMT) during invasion of intestinal tumours, but their role in normal intestinal homeostasis is unknown. Studies in breast and skin epithelia indicate that Snail proteins promote an undifferentiated state. Here, we demonstrate that conditional knockout of SNAI1 in the intestinal epithelium results in apoptotic loss of crypt base columnar stem cells and bias towards differentiation of secretory lineages. In vitro organoid cultures derived from SNAI1 conditional knockout mice also undergo apoptosis when SNAI1 is deleted. Conversely, ectopic expression of SNAI1 in the intestinal epithelium in vivo results in the expansion of the crypt base columnar cell pool and a decrease in secretory enteroendocrine and Paneth cells. Following conditional deletion of SNAI1, the intestinal epithelium fails to produce a proliferative response following radiation-induced damage indicating a fundamental requirement for SNAI1 in epithelial regeneration. These results demonstrate that SNAI1 is required for regulation of lineage choice, maintenance of CBC stem cells and regeneration of the intestinal epithelium following damage.
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absence of a major role for the SNAI1 and snai3 genes in regulating skeletal muscle regeneration in mice
PLOS Currents, 2013Co-Authors: Christine R Norton, Ying Chen, Xiang Hua Han, Cara K Bradley, Luke T Krebs, Jeong Kyo Yoon, Thomas GridleyAbstract:Abstract The Snail gene family encodes DNA-binding zinc finger proteins that function as transcriptional repressors. While the SNAI1 and Snai2 genes are required for normal development in mice, Snai3 mutant mice exhibit no obvious abnormalities. The Snai3 gene is expressed at high levels in skeletal muscle. However, we demonstrate by histological analysis that Snai3 null mutant mice exhibit normal skeletal muscle. During hindlimb muscle regeneration after cardiotoxin-mediated injury, the Snai3 null mice exhibited efficient regeneration. To determine whether the Snai3 gene functions redundantly with the SNAI1 gene during skeletal muscle regeneration, we performed hindlimb muscle regeneration in mice with skeletal muscle-specific deletion of the SNAI1 gene on a Snai3 null genetic background. These mice also exhibited efficient regeneration, demonstrating that there is no major role for the SNAI1 and Snai3 genes in regulating skeletal muscle regeneration in mice.
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the SNAI1 and snai2 proteins occupy their own and each other s promoter during chondrogenesis
Biochemical and Biophysical Research Communications, 2013Co-Authors: Ying Chen, Thomas GridleyAbstract:Two Snail family genes, SNAI1 and Snai2, encode E2 box-binding transcriptional repressors that are important for cartilage development during long bone formation in mice. We demonstrated previously that the SNAI1 and Snai2 genes function redundantly, and compensate for each other's loss during mouse chondrogenesis in vivo. A prediction from this genetic data is that the SNAI1 and SNAI2 proteins can bind to each other's promoter to regulate gene expression. Here we demonstrate that expression of SNAI1 and Snai2 RNA and protein is induced during chondrogenic differentiation of cultured mouse ATDC5 cells. Using chromatin immunoprecipitation assays, we then show that endogenous SNAI1 and SNAI2 proteins bind to a subset of E2 boxes in both their own and each other's promoter in differentiating ATDC5 cells. Together with our previous genetic data, these results support the model that expression of the SNAI1 and Snai2 genes is negatively regulated by their protein products occupying each other's promoter during chondrogenesis, and help provide an explanation for the genetic redundancy observed in the mouse loss of function models.
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compensatory regulation of the SNAI1 and snai2 genes during chondrogenesis
Journal of Bone and Mineral Research, 2013Co-Authors: Ying Chen, Thomas GridleyAbstract:Endochondral bone formation is a multistep process during which a cartilage primordium is replaced by mineralized bone. Several genes involved in cartilage and bone development have been identified as target genes for the Snail family of zinc finger transcriptional repressors, and a gain-of-function study has demonstrated that upregulation of SNAI1 activity in mouse long bones caused a reduction in bone length. However, no in vivo loss-of-function studies have been performed to establish whether Snail family genes have an essential, physiological role during normal bone development. We demonstrate here that the SNAI1 and Snai2 genes function redundantly during embryonic long bone development in mice. Deletion of the Snai2 gene, or limb bud-specific conditional deletion of the SNAI1 gene, did not result in obvious defects in the skeleton. However, limb bud-specific SNAI1 deletion on a Snai2 null genetic background resulted in substantial defects in the long bones of the limbs. Long bones of the SNAI1/Snai2 double mutants exhibited defects in chondrocyte morphology and organization, inhibited trabecular bone formation, and delayed ossification. Chondrocyte proliferation was markedly reduced, and transcript levels of genes encoding cell cycle regulators, such as p21(Waf1/Cip1) , were strikingly upregulated in the SNAI1/Snai2 double mutants, suggesting that during chondrogenesis Snail family proteins act to control cell proliferation by mediating expression of cell-cycle regulators. Snai2 transcript levels were increased in SNAI1 mutant femurs, whereas SNAI1 transcript levels were increased in Snai2 mutant femurs. In addition, in the mutant femurs the SNAI1 and Snai2 genes compensated for each other's loss not only quantitatively, but also by expanding their expression into the other genes' normal expression domains. These results demonstrate that the SNAI1 and Snai2 genes transcriptionally compensate temporally, spatially, and quantitatively for each other's loss, and demonstrate an essential role for Snail family genes during chondrogenesis in mice.
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epiblast specific SNAI1 deletion results in embryonic lethality due to multiple vascular defects
BMC Research Notes, 2009Co-Authors: Hilda Lomeli, Christa Starling, Thomas GridleyAbstract:Members of the Snail gene family, which encode zinc finger proteins that function as transcriptional repressors, play essential roles during embryonic development in vertebrates. Mouse embryos with conditional deletion of the Snail1 (SNAI1) gene in the epiblast, but not in most extraembryonic membranes, exhibit defects in left-right asymmetry specification and migration of mesoderm cells through the posterior primitive streak. Here we describe phenotypic defects that result in death of the mutant embryos by 9.5 days of gestation. Endothelial cells differentiated in epiblast-specific SNAI1-deficient embryos, but formation of an interconnected vascular network was abnormal. To determine whether the observed vascular defects were dependent on disruption of blood flow, we analyzed vascular remodeling in cultured allantois explants from the mutant embryos. Similar vascular defects were observed in the mutant allantois explants. These studies demonstrate that lethality in the SNAI1-conditional mutant embryos is caused by multiple defects in the cardiovascular system.
Didier Y R Stainier - One of the best experts on this subject based on the ideXlab platform.
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the emt transcription factor SNAI1 maintains myocardial wall integrity by repressing intermediate filament gene expression
eLife, 2021Co-Authors: Alessandra Gentile, Anabela Bensimonbrito, Rashmi Priya, Hansmartin Maischein, Janett Piesker, Stefan Guenther, Felix Gunawan, Didier Y R StainierAbstract:The transcription factor SNAI1, a well-known regulator of epithelial-to-mesenchymal transition, has been implicated in early cardiac morphogenesis as well as in cardiac valve formation. However, a role for SNAI1 in regulating other aspects of cardiac morphogenesis has not been reported. Using genetic, transcriptomic, and chimeric analyses in zebrafish, we find that SNAI1b is required in cardiomyocytes for myocardial wall integrity. Loss of SNAI1b increases the frequency of cardiomyocyte extrusion away from the cardiac lumen. Extruding cardiomyocytes exhibit increased actomyosin contractility basally as revealed by enrichment of p-myosin and α-catenin epitope α-18, as well as disrupted intercellular junctions. Transcriptomic analysis of wild-type and SNAI1b mutant hearts revealed the dysregulation of intermediate filament genes, including desmin b (desmb) upregulation. Cardiomyocyte-specific desmb overexpression caused increased cardiomyocyte extrusion, recapitulating the SNAI1b mutant phenotype. Altogether, these results indicate that SNAI1 maintains the integrity of the myocardial epithelium, at least in part by repressing desmb expression.
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the emt transcription factor SNAI1 maintains myocardial wall integrity by repressing intermediate filament gene expression
bioRxiv, 2020Co-Authors: Alessandra Gentile, Anabela Bensimonbrito, Rashmi Priya, Hansmartin Maischein, Janett Piesker, Stefan Guenther, Felix Gunawan, Didier Y R StainierAbstract:The zinc finger transcription factor SNAI1 is a well-known regulator of epithelial-to-mesenchymal transition (EMT)1, 2; it is required for mesoderm ingression in flies3 and neural crest delamination in vertebrates4. During cardiac development, SNAI1-regulated EMT is necessary for myocardial precursor migration and valve formation5, 6. However, a role for SNAI1 in maturing cardiomyocytes (CMs) has not been reported. Here, using genetic, transcriptomic and chimeric analyses in zebrafish, we find that SNAI1b is required for myocardial wall integrity. Global loss of SNAI1b leads to the extrusion of CMs away from the cardiac lumen, a process we show is dependent on cardiac contractility. Examining CM junctions in SNAI1b mutants, we observed that N-cadherin localization was compromised, thereby likely weakening cell-cell adhesion. In addition, extruding CMs exhibit increased actomyosin contractility basally, as revealed by the specific enrichment of canonical markers of actomyosin tension - phosphorylated myosin light chain (active myosin) and the α-catenin epitope α-18. By comparing the transcriptome of wild-type and SNAI1b mutant hearts at early stages of CM extrusion, we found the dysregulation of intermediate filament genes in mutants including the upregulation of desmin b. We tested the role of desmin b in myocardial wall integrity and found that CM-specific desmin b overexpression led to CM extrusion, recapitulating the SNAI1b mutant phenotype. Altogether, these results indicate that SNAI1 is a critical regulator of intermediate filament gene expression in CMs, and that it maintains the integrity of the myocardial epithelium during embryogenesis, at least in part by repressing desmin b expression.
Amparo Cano - One of the best experts on this subject based on the ideXlab platform.
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loxl2 drives epithelial mesenchymal transition via activation of ire1 xbp1 signalling pathway
Scientific Reports, 2017Co-Authors: Eva P Cuevas, Amparo Cano, Gema Morenobueno, Pilar Eraso, Maria J Mazon, Vanesa Santos, Francisco PortilloAbstract:Epithelial-to-Mesenchymal Transition (EMT) is a key process contributing to the aggressiveness of cancer cells. EMT is triggered by activation of different transcription factors collectively known as EMT-TFs. Different cellular cues and cell signalling networks activate EMT at transcriptional and posttranscriptional level in different biological and pathological situations. Among them, overexpression of LOXL2 (lysyl oxidase-like 2) induces EMT independent of its catalytic activity. Remarkably, perinuclear/cytoplasmic accumulation of LOXL2 is a poor prognosis marker of squamous cell carcinomas and is associated to basal breast cancer metastasis by mechanisms no yet fully understood. Here, we report that overexpression of LOXL2 promotes its accumulation in the Endoplasmic Reticulum where it interacts with HSPA5 leading to activation of the IRE1-XBP1 signalling pathway of the ER-stress response. LOXL2-dependent IRE1-XBP1 activation induces the expression of several EMT-TFs: SNAI1, SNAI2, ZEB2 and TCF3 that are direct transcriptional targets of XBP1. Remarkably, inhibition of IRE1 blocks LOXL2-dependent upregulation of EMT-TFs thus hindering EMT induction.
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pai 1 and functional blockade of SNAI1 in breast cancer cell migration
Breast Cancer Research, 2008Co-Authors: Elizabeth Fabreguillevin, Amparo Cano, Gema Morenobueno, Michel Malo, Amandine Cartiermichaud, Hector Peinado, Benoit Vallee, Daniel A Lawrence, Jose Palacios, Georgia BarlovatzmeimonAbstract:Introduction Snail, a family of transcriptional repressors implicated in cell movement, has been correlated with tumour invasion. The Plasminogen Activation (PA) system, including urokinase plasminogen activator (uPA), its receptor and its inhibitor, plasminogen activator inhibitor type 1(PAI-1), also plays a key role in cancer invasion and metastasis, either through proteolytic degradation or by non-proteolytic modulation of cell adhesion and migration. Thus, Snail and the PA system are both over-expressed in cancer and influence this process. In this study we aimed to determine if the activity of SNAI1 (a member of the Snail family) is correlated with expression of the PA system components and how this correlation can influence tumoural cell migration.
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SNAI1 and Snai2 collaborate on tumor growth and metastasis properties of mouse skin carcinoma cell lines
Oncogene, 2008Co-Authors: David Olmeda, Amalia Montes, Gema Moreno-bueno, Juana M. Flores, Francisco García-del Portillo, Amparo CanoAbstract:SNAI1 (Snail) and Snai2 (Slug), the two main members of Snail family factors, are important mediators of epithelial-mesenchymal transitions and involved in tumor progression. We recently reported that SNAI1 plays a major role in tumor growth, invasion and metastasis, but the contribution of Snai2 to tumorigenesis is not yet well understood. To approach this question we have silenced Snai2 and/or SNAI1 by stable RNA interference in two independent mouse skin carcinoma (HaCa4 and CarB) cell lines. We demonstrate that Snai2 knockdown has a milder effect, but collaborates with SNAI1 silencing in reduction of tumor growth potential of either carcinoma cell line when injected into nude mice. Importantly, SNAI1 or Snai2 silencing dramatically influences the metastatic ability of squamous carcinoma HaCa4 cells, inducing a strong reduction in liver and lung distant metastasis. However, only SNAI1 knockdown has an effective action on invasiveness and fully abolishes tumor cell dissemination into the spleen. These results demonstrate that SNAI1 and Snai2 collaborate on primary tumor growth and specifically contribute to site-specific metastasis of HaCa4 cells. These data also indicate that SNAI1 is the major regulator of local invasion, supporting a hierarchical participation of both factors in the metastatic process.
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SNAI1 is required for tumor growth and lymph node metastasis of human breast carcinoma mda mb 231 cells
Cancer Research, 2007Co-Authors: David Olmeda, Juana M. Flores, Gema Morenobueno, Angels Fabra, Francisco Portillo, Amparo CanoAbstract:The transcription factor, SNAI1 (Snail), has recently been proposed as an important mediator of tumor invasion because of its role in E-cadherin down-regulation and induction of epithelial-mesenchymal transition. In human breast cancer, the expression of SNAI1 and/or the homologous SNAI2 (Slug) has been associated with E-cadherin repression, local or distant metastasis, tumor recurrence, or poor prognosis in different tumor series. However, the specific contribution of either factor to breast tumor progression is still unclear. We have analyzed the role of SNAI1 in human breast cancer by loss of function studies and provide evidence of a major role for SNAI1 in both primary tumor growth and metastasis of human breast carcinoma MDA-MB-231 cells. Specific silencing of SNAI1 by short hairpin RNA induces a decrease in mesenchymal and proinvasive markers (MMP9, ID1, SPARC) in MDA-MB-231 cells, concomitant with reduced in vitro invasive behavior. More importantly, stable SNAI1 silencing in MDA-MB-231 cells leads to a dramatic reduction of in vivo tumor incidence and growth rate. Tumors induced by MDA-MB-231-SNAI1–silenced cells show extensive necrotic regions and a significant decrease in invasive and angiogenic markers. Moreover, SNAI1 silencing increases the sensitivity of MDA-MB-231 cells to chemotherapeutics relevant in breast cancer treatments, gemcitabine and docetaxel. Remarkably, analysis of cell lines derived from lymph node metastasis indicates that SNAI1 expression is required for metastatic dissemination. [Cancer Res 2007;67(24):11721–31]
Katja Horvay - One of the best experts on this subject based on the ideXlab platform.
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microarray profiling to analyze the effect of SNAI1 loss in mouse intestinal epithelium
Genomics data, 2015Co-Authors: Gary R Hime, Katja Horvay, Thierry Jarde, Franca Casagranda, Victoria M Perreau, Helen E AbudAbstract:Epithelial stem cells from a variety of tissues have been shown to express genes linked to mesenchymal cell states. The Snail family of transcriptional factors has long been regarded as a marker of mesenchymal cells, however recent studies have indicated an involvement in regulation of epithelial stem cell populations. SNAI1 is expressed in the stem cell population found at the base of the mouse small intestinal crypt that is responsible for generating all differentiated cell types of the intestinal epithelium. We utilized an inducible Cre recombinase approach in the intestinal epithelium combined with a conditional floxed SNAI1 allele to induce knockout of gene function in the stem cell population. Loss of SNAI1 resulted in loss of crypt base columnar cells and a failure to induce a proliferative response following radiation damage. We induced SNAI1 loss in cultured organoids that had been derived from epithelial cells and compared gene expression to organoids with functional SNAI1. Here we describe in detail the methods for generation of knockout organoids and analysis of microarray data that has been deposited in Gene Expression Omnibus (GEO):GSE65005.
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SNAI1 regulates cell lineage allocation and stem cell maintenance in the mouse intestinal epithelium
The EMBO Journal, 2015Co-Authors: Katja Horvay, Thierry Jarde, Franca Casagranda, Victoria M Perreau, Katharina Haigh, Christian M Nefzger, Reyhan Akhtar, Thomas Gridley, Geert BerxAbstract:Snail family members regulate epithelial-to-mesenchymal transition (EMT) during invasion of intestinal tumours, but their role in normal intestinal homeostasis is unknown. Studies in breast and skin epithelia indicate that Snail proteins promote an undifferentiated state. Here, we demonstrate that conditional knockout of SNAI1 in the intestinal epithelium results in apoptotic loss of crypt base columnar stem cells and bias towards differentiation of secretory lineages. In vitro organoid cultures derived from SNAI1 conditional knockout mice also undergo apoptosis when SNAI1 is deleted. Conversely, ectopic expression of SNAI1 in the intestinal epithelium in vivo results in the expansion of the crypt base columnar cell pool and a decrease in secretory enteroendocrine and Paneth cells. Following conditional deletion of SNAI1, the intestinal epithelium fails to produce a proliferative response following radiation-induced damage indicating a fundamental requirement for SNAI1 in epithelial regeneration. These results demonstrate that SNAI1 is required for regulation of lineage choice, maintenance of CBC stem cells and regeneration of the intestinal epithelium following damage.
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wnt signaling regulates SNAI1 expression and cellular localization in the mouse intestinal epithelial stem cell niche
Stem Cells and Development, 2011Co-Authors: Katja Horvay, Franca Casagranda, Agnes Gany, Gary R Hime, Helen E AbudAbstract:Snail genes are transcriptional repressors well known to play important roles in epithelial to mesenchymal transitions during both embryogenesis and cancer metastasis. Although they are generally regarded as markers of mesenchymal cells, Snail genes have also recently been implicated in regulating stem cell populations in both Drosophila and vertebrates. In this study we investigate SNAI1, a member of the mouse Snail family, in the intestinal stem cell niche and examine the relationship between canonical Wnt signaling, a key regulatory pathway of intestinal stem cells, and expression and cellular localization of SNAI1. Strong nuclear expression of SNAI1 was detected in the crypt base columnar stem cells in the adult small intestine while SNAI1 was mostly found in the cytoplasm of differentiated enterocytes and enteroendocrine cells. Expression and cellular localization of SNAI1 in the intestinal epithelium appears to be regulated by the canonical Wnt signaling pathway as SNAI1 expression was dramatically reduced after conditional deletion of β-catenin. Conversely, significant nuclear SNAI1 was detected in polyps derived from Apc(min) mice and in intestinal villi after conditional mutation of Apc in AhCre, Apc(f/f) mice, indicating that upregulation of the Wnt pathway in the intestinal epithelium induces both increased expression and nuclear localization of SNAI1.
Alessandra Gentile - One of the best experts on this subject based on the ideXlab platform.
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the emt transcription factor SNAI1 maintains myocardial wall integrity by repressing intermediate filament gene expression
eLife, 2021Co-Authors: Alessandra Gentile, Anabela Bensimonbrito, Rashmi Priya, Hansmartin Maischein, Janett Piesker, Stefan Guenther, Felix Gunawan, Didier Y R StainierAbstract:The transcription factor SNAI1, a well-known regulator of epithelial-to-mesenchymal transition, has been implicated in early cardiac morphogenesis as well as in cardiac valve formation. However, a role for SNAI1 in regulating other aspects of cardiac morphogenesis has not been reported. Using genetic, transcriptomic, and chimeric analyses in zebrafish, we find that SNAI1b is required in cardiomyocytes for myocardial wall integrity. Loss of SNAI1b increases the frequency of cardiomyocyte extrusion away from the cardiac lumen. Extruding cardiomyocytes exhibit increased actomyosin contractility basally as revealed by enrichment of p-myosin and α-catenin epitope α-18, as well as disrupted intercellular junctions. Transcriptomic analysis of wild-type and SNAI1b mutant hearts revealed the dysregulation of intermediate filament genes, including desmin b (desmb) upregulation. Cardiomyocyte-specific desmb overexpression caused increased cardiomyocyte extrusion, recapitulating the SNAI1b mutant phenotype. Altogether, these results indicate that SNAI1 maintains the integrity of the myocardial epithelium, at least in part by repressing desmb expression.
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the emt transcription factor SNAI1 maintains myocardial wall integrity by repressing intermediate filament gene expression
bioRxiv, 2020Co-Authors: Alessandra Gentile, Anabela Bensimonbrito, Rashmi Priya, Hansmartin Maischein, Janett Piesker, Stefan Guenther, Felix Gunawan, Didier Y R StainierAbstract:The zinc finger transcription factor SNAI1 is a well-known regulator of epithelial-to-mesenchymal transition (EMT)1, 2; it is required for mesoderm ingression in flies3 and neural crest delamination in vertebrates4. During cardiac development, SNAI1-regulated EMT is necessary for myocardial precursor migration and valve formation5, 6. However, a role for SNAI1 in maturing cardiomyocytes (CMs) has not been reported. Here, using genetic, transcriptomic and chimeric analyses in zebrafish, we find that SNAI1b is required for myocardial wall integrity. Global loss of SNAI1b leads to the extrusion of CMs away from the cardiac lumen, a process we show is dependent on cardiac contractility. Examining CM junctions in SNAI1b mutants, we observed that N-cadherin localization was compromised, thereby likely weakening cell-cell adhesion. In addition, extruding CMs exhibit increased actomyosin contractility basally, as revealed by the specific enrichment of canonical markers of actomyosin tension - phosphorylated myosin light chain (active myosin) and the α-catenin epitope α-18. By comparing the transcriptome of wild-type and SNAI1b mutant hearts at early stages of CM extrusion, we found the dysregulation of intermediate filament genes in mutants including the upregulation of desmin b. We tested the role of desmin b in myocardial wall integrity and found that CM-specific desmin b overexpression led to CM extrusion, recapitulating the SNAI1b mutant phenotype. Altogether, these results indicate that SNAI1 is a critical regulator of intermediate filament gene expression in CMs, and that it maintains the integrity of the myocardial epithelium during embryogenesis, at least in part by repressing desmin b expression.