scholarly journals ATXN10 Is Required for Embryonic Heart Development and Maintenance of Epithelial Cell Phenotypes in the Adult Kidney and Pancreas

2021 ◽  
Vol 9 ◽  
Author(s):  
Melissa R. Bentley-Ford ◽  
Reagan S. Andersen ◽  
Mandy J. Croyle ◽  
Courtney J. Haycraft ◽  
Kelsey R. Clearman ◽  
...  
Keyword(s):  
Heart Development ◽  
Epithelial To Mesenchymal Transition ◽  
Pancreatic Insufficiency ◽  
Joubert Syndrome ◽  
Embryonic Lethality ◽  
Mesenchymal Transition ◽  
Adult Mice ◽  
Adult Kidney ◽  
Cilia Formation ◽  
Acinar To Ductal Metaplasia

Atxn10 is a gene known for its role in cytokinesis and is associated with spinocerebellar ataxia (SCA10), a slowly progressing cerebellar syndrome caused by an intragenic pentanucleotide repeat expansion. Atxn10 is also implicated in the ciliopathy syndromes nephronophthisis (NPHP) and Joubert syndrome (JBTS), which are caused by the disruption of cilia function leading to nephron loss, impaired renal function, and cerebellar hypoplasia. How Atxn10 disruption contributes to these disorders remains unknown. Here, we generated Atxn10 congenital and conditional mutant mouse models. Our data indicate that while ATXN10 protein can be detected around the base of the cilium as well as in the cytosol, its loss does not cause overt changes in cilia formation or morphology. Congenital loss of Atxn10 results in embryonic lethality around E10.5 associated with pericardial effusion and loss of trabeculation. Similarly, tissue-specific loss of ATXN10 in the developing endothelium (Tie2-Cre) and myocardium (cTnT-Cre) also results in embryonic lethality with severe cardiac malformations occurring in the latter. Using an inducible Cagg-CreER to disrupt ATXN10 systemically at postnatal stages, we show that ATXN10 is also required for survival in adult mice. Loss of ATXN10 results in severe pancreatic and renal abnormalities leading to lethality within a few weeks post ATXN10 deletion in adult mice. Evaluation of these phenotypes further identified rapid epithelial-to-mesenchymal transition (EMT) in these tissues. In the pancreas, the phenotype includes signs of both acinar to ductal metaplasia and EMT with aberrant cilia formation and severe defects in glucose homeostasis related to pancreatic insufficiency or defects in feeding or nutrient intake. Collectively, this study identifies ATXN10 as an essential protein for survival.

scholarly journals ATXN10 is required for embryonic heart development and maintenance of epithelial cell phenotypes in the adult kidney and pancreas

2021 ◽  
Author(s):  
Melissa R. Bentley-Ford ◽  
Reagan S. Andersen ◽  
Mandy J. Croyle ◽  
Courtney J. Haycraft ◽  
Kelsey R. Clearman ◽  
...  
Keyword(s):  
Heart Development ◽  
Epithelial To Mesenchymal Transition ◽  
Pancreatic Insufficiency ◽  
Joubert Syndrome ◽  
Embryonic Lethality ◽  
Mesenchymal Transition ◽  
Adult Mice ◽  
Adult Kidney ◽  
Cilia Formation ◽  
Acinar To Ductal Metaplasia

AbstractAtxn10 is a gene known for its role in cytokinesis during the cell cycle and is associated with Spinocerebellar Ataxia (SCA10), a slowly progressing cerebellar syndrome caused by an intragenic pentanucleotide repeat expansion. Atxn10 is also implicated in the ciliopathy syndromes Nephronophthisis (NPHP) and Joubert Syndrome (JBTS), which are caused by disruption of cilia function leading to nephron loss, impaired renal function, and cerebellar hypoplasia. How Atxn10 disruption contributes to these disorders remains unknown. Here we generated Atxn10 congenital and conditional mutant mouse models. Our data indicate that while ATXN10 protein can be detected around the base of the cilium as well as in the cytosol, its loss does not cause overt changes in cilia formation or morphology. Congenital loss of Atxn10 results in embryonic lethality around E10.5 associated with pericardial effusion and loss of trabeculation. Similarly, tissue specific loss of ATXN10 in the developing endothelium (Tie2-Cre) and myocardium (cTnT-Cre) also results in embryonic lethality with severe cardiac malformations occurring in the latter. Using an inducible Cagg-CreER to disrupt Atxn10 systemically, we show that ATXN10 is also required for survival in adult mice. Loss of ATXN10 results in severe pancreatic and renal abnormalities leading to lethality within a few weeks post ATXN10 deletion in adult mice. Evaluation of these phenotypes further identified rapid epithelial to mesenchymal transition (EMT) in these tissues. In the pancreas, the phenotype includes signs of both acinar to ductal metaplasia and EMT with aberrant cilia formation and severe defects in glucose homeostasis related to pancreatic insufficiency or defects in feeding or nutrient intake. Collectively this study identifies ATXN10 as an essential protein for survival.

scholarly journals Vegfaa instructs cardiac muscle hyperplasia in adult zebrafish

2018 ◽  
Vol 115 (35) ◽  
pp. 8805-8810 ◽  
Author(s):  
Ravi Karra ◽  
Matthew J. Foglia ◽  
Wen-Yee Choi ◽  
Christine Belliveau ◽  
Paige DeBenedittis ◽  
...  
Keyword(s):  
Heart Development ◽  
Epithelial To Mesenchymal Transition ◽  
Cardiac Injury ◽  
Angiogenic Factor ◽  
Regulatory Sequences ◽  
Mesenchymal Transition ◽  
Epicardial Cells ◽  
Myocardial Wall ◽  
Tightly Coupled ◽  
Spatiotemporal Control

During heart development and regeneration, coronary vascularization is tightly coupled with cardiac growth. Although inhibiting vascularization causes defects in the innate regenerative response of zebrafish to heart injury, angiogenic signals are not known to be sufficient for triggering regeneration events. Here, by using a transgenic reporter strain, we found that regulatory sequences of the angiogenic factor vegfaa are active in epicardial cells of uninjured animals, as well as in epicardial and endocardial tissue adjacent to regenerating muscle upon injury. Additionally, we find that induced cardiac overexpression of vegfaa in zebrafish results in overt hyperplastic thickening of the myocardial wall, accompanied by indicators of angiogenesis, epithelial-to-mesenchymal transition, and cardiomyocyte regeneration programs. Unexpectedly, vegfaa overexpression in the context of cardiac injury enabled ectopic cardiomyogenesis but inhibited regeneration at the site of the injury. Our findings identify Vegfa as one of a select few known factors sufficient to activate adult cardiomyogenesis, while also illustrating how instructive factors for heart regeneration require spatiotemporal control for efficacy.

scholarly journals SRSF3 is a key regulator of epicardial formation

2021 ◽  
Author(s):  
Irina-Elena Lupu ◽  
Andia Nicole Redpath ◽  
Nicola Smart
Keyword(s):  
Heart Development ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Cellular Proliferation ◽  
Rna Binding ◽  
Cardiac Development ◽  
Cardiac Fibroblasts ◽  
Mesenchymal Transition ◽  
Epicardial Cells ◽  
Epicardial Layer

The epicardium is a fundamental regulator of cardiac development, functioning to secrete essential growth factors and to produce epicardium-derived cells (EPDCs) that contribute most coronary vascular smooth muscle cells and cardiac fibroblasts. The molecular mechanisms that control epicardial formation and proliferation have not been fully elucidated. In this study, we found that the RNA-binding protein SRSF3 is highly expressed in the proepicardium and later in the epicardial layer during heart development. Deletion of Srsf3 from the murine proepicardium using the Tg(Gata5-Cre) or embryonic day (E) 8.5 induction of Wt1CreERT2 led to proliferative arrest and impaired epithelial-to-mesenchymal transition (EMT), which prevented proper formation and function of the epicardial layer. Induction of Srsf3 deletion with the Wt1CreERT2 after the proepicardial stage resulted in impaired EPDC formation and epicardial proliferation at E13.5. Single-cell RNA-sequencing showed SRSF3-depleted epicardial cells were removed by E15.5 and the remaining non-recombined cells became hyperproliferative and compensated for the loss via up-regulation of Srsf3. This research identifies SRSF3 as a master regulator of cellular proliferation in epicardial cells.

scholarly journals The Role of the Epicardium During Heart Development and Repair

2020 ◽  
Vol 126 (3) ◽  
pp. 377-394 ◽  
Author(s):  
Pearl Quijada ◽  
Michael A. Trembley ◽  
Eric M. Small
Keyword(s):  
Heart Development ◽  
Progenitor Cell ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Cardiac Injury ◽  
Single Layer ◽  
Mesenchymal Transition ◽  
Heart Repair ◽  
Heart Formation

The heart is lined by a single layer of mesothelial cells called the epicardium that provides important cellular contributions for embryonic heart formation. The epicardium harbors a population of progenitor cells that undergo epithelial-to-mesenchymal transition displaying characteristic conversion of planar epithelial cells into multipolar and invasive mesenchymal cells before differentiating into nonmyocyte cardiac lineages, such as vascular smooth muscle cells, pericytes, and fibroblasts. The epicardium is also a source of paracrine cues that are essential for fetal cardiac growth, coronary vessel patterning, and regenerative heart repair. Although the epicardium becomes dormant after birth, cardiac injury reactivates developmental gene programs that stimulate epithelial-to-mesenchymal transition; however, it is not clear how the epicardium contributes to disease progression or repair in the adult. In this review, we will summarize the molecular mechanisms that control epicardium-derived progenitor cell migration, and the functional contributions of the epicardium to heart formation and cardiomyopathy. Future perspectives will be presented to highlight emerging therapeutic strategies aimed at harnessing the regenerative potential of the fetal epicardium for cardiac repair.

scholarly journals Deletion of Smad2 in Mouse Liver Reveals Novel Functions in Hepatocyte Growth and Differentiation

2006 ◽  
Vol 26 (2) ◽  
pp. 654-667 ◽  
Author(s):  
Wenjun Ju ◽  
Atsushi Ogawa ◽  
Joerg Heyer ◽  
Dirk Nierhof ◽  
Liping Yu ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Hepatocyte Proliferation ◽  
Mammalian Development ◽  
Mesenchymal Transition ◽  
Functional Roles ◽  
Adult Mice ◽  
Hepatocyte Growth

ABSTRACT Smad family proteins Smad2 and Smad3 are activated by transforming growth factor β (TGF-β)/activin/nodal receptors and mediate transcriptional regulation. Although differential functional roles of Smad2 and Smad3 are apparent in mammalian development, the relative functional roles of Smad2 and Smad3 in postnatal systems remain unclear. We used Cre/loxP-mediated gene targeting for hepatocyte-specific deletion of Smad2 (S2HeKO) in adult mice and generated hepatocyte-selective Smad2/Smad3 double knockouts by intercrossing AlbCre/Smad2f/f (S2HeKO) and Smad3-deficient Smad3ex8/ex8 (S3KO) mice. All strains were viable and had normal adult liver. However, necrogenic CCL4-induced hepatocyte proliferation was significantly increased in S2HeKO compared to Ctrl and S3KO livers, and transplanted S2HeKO hepatocytes repopulated recipient liver at dramatically increased rates compared to Ctrl hepatocytes in vivo. Using primary hepatocytes, we found that TGF-β-induced G1 arrest, apoptosis, and epithelial-to-mesenchymal transition in Ctrl and S2HeKO but not in S3KO hepatocytes. Interestingly, S2HeKO cells spontaneously acquired mesenchymal features characteristic of epithelial-to-mesenchymal transition (EMT). Collectively, these results demonstrate that Smad2 suppresses hepatocyte growth and dedifferentiation independent of TGF-β signaling. Smad2 is not required for TGF-β-stimulated apoptosis, EMT, and growth inhibition in hepatocytes.

scholarly journals Epicardial Epithelial-to-Mesenchymal Transition in Heart Development and Disease

2016 ◽  
Vol 5 (2) ◽  
pp. 27 ◽  
Author(s):  
Michael Krainock ◽  
Omar Toubat ◽  
Soula Danopoulos ◽  
Allison Beckham ◽  
David Warburton ◽  
...  
Keyword(s):  
Heart Development ◽  
Epithelial To Mesenchymal Transition ◽  
Mesenchymal Transition

scholarly journals A novel function for HEG1 in promoting metastasis in hepatocellular carcinoma

2019 ◽  
Vol 133 (19) ◽  
pp. 2019-2022 ◽  
Author(s):  
Brittany Dewdney ◽  
Lionel Hebbard
Keyword(s):  
Hepatocellular Carcinoma ◽  
Heart Development ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Biological Function ◽  
Secondary Site ◽  
Tumour Resection ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Therapeutic Research

Abstract Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related deaths around the globe. For patients receiving liver tumour resection, the risk of reoccurrence and metastasis is high. Cancer metastasis can occur as a consequence of a physical change known as epithelial to mesenchymal transition (EMT). In this instance, cancer cells acquire migratory and invasive characteristics that allow the cells to move into adjacent tissue or enter the bloodstream to reach a secondary site, where they begin to form a new tumour. Targetting proteins involved in the signalling pathways that induce the mesenchymal phenotype has been an ongoing field of research. A recently published study has described a novel role for the heart development protein with EGF-like domains (HEG1) in promoting EMT. This research provides new insights into the biological function of this protein in HCC. Furthermore, the research indicates a new target for future prognostic and therapeutic research in HCC.

scholarly journals miR-200c-3p Regulates Epitelial-to-Mesenchymal Transition in Epicardial Mesothelial Cells by Targeting Epicardial Follistatin-Related Protein 1

2021 ◽  
Vol 22 (9) ◽  
pp. 4971
Author(s):  
Elena Pontemezzo ◽  
Eleonora Foglio ◽  
Enza Vernucci ◽  
Alessandra Magenta ◽  
Marco D’Agostino ◽  
...  
Keyword(s):  
Heart Development ◽  
Epithelial To Mesenchymal Transition ◽  
Cardiac Tissue ◽  
Mesothelial Cells ◽  
Luciferase Reporter ◽  
Related Protein ◽  
Mesenchymal Transition ◽  
And Migration ◽  
Tgf Β1

Recent findings suggest that epithelial to mesenchymal transition (EMT), a key step during heart development, is involved in cardiac tissue repair following myocardial infarction (MI). MicroRNAs (miRNAs) act as key regulators in EMT processes; however, the mechanisms by which miRNAs target epicardial EMT remain largely unknown. Here, by using an in vitro model of epicardial EMT, we investigated the role of miRNAs as regulators of this process and their potential targets. EMT was induced in murine epicardial-mesothelial cells (EMCs) through TGF β1 treatment for 48, 72, and 96 h as indicated by the expression of EMT-related genes by qRT-PCR, WB, and immunofluorescence. Further, enhanced expression of stemness genes was also detected. Among several EMT-related miRNAs, miR-200c-3p expression resulted as the most strongly suppressed. Interestingly, we also found a significant upregulation of Follistatin-related protein 1 (FSTL1), a miR-200c predicted target already identified as a potent cardiogenic factor produced by epicardial cells that promotes regeneration following MI. Dual-luciferase reporter assay demonstrated that miR-200c-3p directly targeted the 3′-untranslated region of FSTL1 in EMCs. Consistently, WB analysis showed that knockdown of miR-200c-3p significantly increased FSTL1 expression, whereas overexpression of miR-200c-3p counteracted TGF β1-mediated FSTL1 upregulation. Importantly, FSTL1 silencing maintained epithelial features in EMCs, despite EMT induction by TGF β1, and attenuated EMT-associated traits, including migration and stemness. In conclusion, epicardial FSTL1, an important cardiogenic factor in its secreted form, induces EMT, stemness, and migration of EMCs in a miR-200c-3p dependent pathway.

The role of DUBs in the post-translational control of cell migration

2019 ◽  
Vol 63 (5) ◽  
pp. 579-594 ◽  
Author(s):  
Guillem Lambies ◽  
Antonio García de Herreros ◽  
Víctor M. Díaz
Keyword(s):  
Cell Migration ◽  
Translational Control ◽  
Epithelial To Mesenchymal Transition ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling ◽  
Mesenchymal Transition ◽  
Tgfβ Receptors ◽  
Fundamental Process ◽  
Multistep Process

Abstract Cell migration is a multifactorial/multistep process that requires the concerted action of growth and transcriptional factors, motor proteins, extracellular matrix remodeling and proteases. In this review, we focus on the role of transcription factors modulating Epithelial-to-Mesenchymal Transition (EMT-TFs), a fundamental process supporting both physiological and pathological cell migration. These EMT-TFs (Snail1/2, Twist1/2 and Zeb1/2) are labile proteins which should be stabilized to initiate EMT and provide full migratory and invasive properties. We present here a family of enzymes, the deubiquitinases (DUBs) which have a crucial role in counteracting polyubiquitination and proteasomal degradation of EMT-TFs after their induction by TGFβ, inflammatory cytokines and hypoxia. We also describe the DUBs promoting the stabilization of Smads, TGFβ receptors and other key proteins involved in transduction pathways controlling EMT.

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