23 results on '"Iván M. Moya"'
Search Results
2. In Vivo Tracking and 3D Mapping of Cell Death in Regeneration and Cancer Using Trypan Blue
- Author
-
Nicole Procel, Karen Camacho, Elisabeth Verboven, Isabel Baroja, Priscila A. Guerrero, Hanne Hillen, Carlos Estrella-García, Nicole Vizcaíno-Rodríguez, Leticia Sansores-Garcia, Ana Santamaría-Naranjo, Andrés Romero-Carvajal, Andrés Caicedo, Georg Halder, and Iván M. Moya
- Subjects
in vivo cell death tracking ,Trypan Blue labeling ,organ regeneration ,anticancer therapy assessment ,ischemia-reperfusion injury ,cholangiocarcinoma ,Cytology ,QH573-671 - Abstract
Tracking cell death in vivo can enable a better understanding of the biological mechanisms underlying tissue homeostasis and disease. Unfortunately, existing cell death labeling methods lack compatibility with in vivo applications or suffer from low sensitivity, poor tissue penetration, and limited temporal resolution. Here, we fluorescently labeled dead cells in vivo with Trypan Blue (TBlue) to detect single scattered dead cells or to generate whole-mount three-dimensional maps of large areas of necrotic tissue during organ regeneration. TBlue effectively marked different types of cell death, including necrosis induced by CCl4 intoxication in the liver, necrosis caused by ischemia-reperfusion in the skin, and apoptosis triggered by BAX overexpression in hepatocytes. Moreover, due to its short circulating lifespan in blood, TBlue labeling allowed in vivo “pulse and chase” tracking of two temporally spaced populations of dying hepatocytes in regenerating mouse livers. Additionally, upon treatment with cisplatin, TBlue labeled dead cancer cells in livers with cholangiocarcinoma and dead thymocytes due to chemotherapy-induced toxicity, showcasing its utility in assessing anticancer therapies in preclinical models. Thus, TBlue is a sensitive and selective cell death marker for in vivo applications, facilitating the understanding of the fundamental role of cell death in normal biological processes and its implications in disease.
- Published
- 2024
- Full Text
- View/download PDF
3. Comparison of the Opn-CreER and Ck19-CreER Drivers in Bile Ducts of Normal and Injured Mouse Livers
- Author
-
Bram Lesaffer, Elisabeth Verboven, Leen Van Huffel, Iván M. Moya, Leo A. van Grunsven, Isabelle A. Leclercq, Frédéric P. Lemaigre, and Georg Halder
- Subjects
Cre ,cholangiocytes ,bile duct cells ,knockout ,mouse liver ,lineage tracing ,Opn ,Ck19 ,Cytology ,QH573-671 - Abstract
Inducible cyclization recombinase (Cre) transgenic mouse strains are powerful tools for cell lineage tracing and tissue-specific knockout experiments. However, low efficiency or leaky expression can be important pitfalls. Here, we compared the efficiency and specificity of two commonly used cholangiocyte-specific Cre drivers, the Opn-iCreERT2 and Ck19-CreERT drivers, using a tdTomato reporter strain. We found that Opn-iCreERT2 triggered recombination of the tdTomato reporter in 99.9% of all cholangiocytes while Ck19-CreERT only had 32% recombination efficiency after tamoxifen injection. In the absence of tamoxifen, recombination was also induced in 2% of cholangiocytes for the Opn-iCreERT2 driver and in 13% for the Ck19-CreERT driver. For both drivers, Cre recombination was highly specific for cholangiocytes since recombination was rare in other liver cell types. Toxic liver injury ectopically activated Opn-iCreERT2 but not Ck19-CreERT expression in hepatocytes. However, ectopic recombination in hepatocytes could be avoided by applying a three-day long wash-out period between tamoxifen treatment and toxin injection. Therefore, the Opn-iCreERT2 driver is best suited for the generation of mutant bile ducts, while the Ck19-CreERT driver has near absolute specificity for bile duct cells and is therefore favorable for lineage tracing experiments.
- Published
- 2019
- Full Text
- View/download PDF
4. YAP and TAZ Heterogeneity in Primary Liver Cancer: An Analysis of Its Prognostic and Diagnostic Role
- Author
-
Matthias Van Haele, Iván M. Moya, Ruçhan Karaman, Guy Rens, Janne Snoeck, Olivier Govaere, Frederik Nevens, Chris Verslype, Baki Topal, Diethard Monbaliu, Georg Halder, and Tania Roskams
- Subjects
HCC ,cHCC-CCA ,CCA ,YAP ,TAZ ,Keratin 19 ,Hepatic progenitor cells ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Primary liver cancer comprises a diverse group of liver tumors. The heterogeneity of these tumors is seen as one of the obstacles to finding an effective therapy. The Hippo pathway, with its downstream transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), has a decisive role in the carcinogenesis of primary liver cancer. Therefore, we examined the expression pattern of YAP and TAZ in 141 patients with hepatocellular carcinoma keratin 19 positive (HCC K19+), hepatocellular carcinoma keratin 19 negative (HCC K19−), combined hepatocellular⁻cholangiocarcinoma carcinoma (cHCC-CCA), or cholangiocarcinoma (CCA). All cHCC-CCA and CCA patients showed high expression levels for YAP and TAZ, while only some patients of the HCC group were positive. Notably, we found that a histoscore of both markers is useful in the challenging diagnosis of cHCC-CCA. In addition, positivity for YAP and TAZ was observed in the hepatocellular and cholangiocellular components of cHCC-CCA, which suggests a single cell origin in cHCC-CCA. Within the K19− HCC group, our results demonstrate that the expression of YAP is a statistically significant predictor of poor prognosis when observed in the cytoplasm. Nuclear expression of TAZ is an even more specific and independent predictor of poor disease-free survival and overall survival of K19− HCC patients. Our results thus identify different levels of YAP/TAZ expression in various liver cancers that can be used for diagnostics.
- Published
- 2019
- Full Text
- View/download PDF
5. Hippo–YAP/TAZ signalling in organ regeneration and regenerative medicine
- Author
-
Iván M. Moya and Georg Halder
- Subjects
0303 health sciences ,Hippo signaling pathway ,Effector ,Signal transducing adaptor protein ,Cell Biology ,Protein Serine-Threonine Kinases ,Biology ,Regenerative Medicine ,Regenerative medicine ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,Animals ,Humans ,Epithelial–mesenchymal transition ,Signal transduction ,Molecular Biology ,Transcription factor ,Developmental biology ,030217 neurology & neurosurgery ,Adaptor Proteins, Signal Transducing ,Signal Transduction ,Transcription Factors ,030304 developmental biology - Abstract
The Hippo pathway and its downstream effectors, the transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), regulate organ growth and cell plasticity during animal development and regeneration. Remarkably, experimental activation of YAP/TAZ in the mouse can promote regeneration in organs with poor or compromised regenerative capacity, such as the adult heart and the liver and intestine of old or diseased mice. However, therapeutic YAP/TAZ activation may cause serious side effects. Most notably, YAP/TAZ are hyperactivated in human cancers, and prolonged activation of YAP/TAZ triggers cancer development in mice. Thus, can the power of YAP/TAZ to promote regeneration be harnessed in a safe way? Here, we review the role of Hippo signalling in animal regeneration, examine the promises and risks of YAP/TAZ activation for regenerative medicine and discuss strategies to activate YAP/TAZ for regenerative therapy while minimizing adverse side effects. ispartof: NATURE REVIEWS MOLECULAR CELL BIOLOGY vol:20 issue:4 pages:211-226 ispartof: location:England status: published
- Published
- 2018
6. Peritumoral activation of the Hippo pathway effectors YAP and TAZ suppresses liver cancer in mice
- Author
-
Panagiotis Karras, Maxime de Waegeneer, Ruchan Karaman, Leticia Sansores-Garcia, Laura Van den Mooter, Inge Mannaerts, Randy L. Johnson, Hanne Hillen, Elisabeth Verboven, Matthias Van Haele, Weronika Kowalczyk, Iván M. Moya, Jun Xie, Tania Roskams, Georg Halder, Jean-Christophe Marine, Leen Van Huffel, Soheil Soheily, Lars Zender, Leo A. van Grunsven, Stefaan Verhulst, Stephanie Anais Castaldo, Ana Algueró-Nadal, Jelle Jacobs, Stein Aerts, Basic (bio-) Medical Sciences, Liver Cell Biology, and Translational Liver Cell Biology
- Subjects
Carcinoma, Hepatocellular ,Cell Survival ,Cell ,Cell Cycle Proteins ,Protein Serine-Threonine Kinases ,Cholangiocarcinoma ,03 medical and health sciences ,Liver Neoplasms, Experimental ,0302 clinical medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Hippo Signaling Pathway ,Melanoma ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,0303 health sciences ,Hippo signaling pathway ,Multidisciplinary ,Hyperactivation ,Chemistry ,Effector ,Liver Neoplasms ,Signal transducing adaptor protein ,YAP-Signaling Proteins ,medicine.disease ,Tumor Burden ,Mice, Inbred C57BL ,medicine.anatomical_structure ,Cell culture ,Transcriptional Coactivator with PDZ-Binding Motif Proteins ,030220 oncology & carcinogenesis ,Hepatocytes ,Trans-Activators ,Cancer research ,Signal transduction ,Liver cancer ,Signal Transduction ,Transcription Factors - Abstract
Mixed signals at tumor margins The Hippo signaling pathway has been implicated in tumor growth, sparking interest in the pathway as a potential therapeutic target. In a study of liver cancer in genetically manipulated mice, Moya et al. discovered that the role of this pathway in tumorigenesis is more complex than previously appreciated. They confirmed that activation of the Hippo pathway within tumor cells drives tumor growth; however, they also found that activation of the pathway in adjacent healthy cells has the opposite effect, suppressing tumor growth. Whether tumor cells survive or are eliminated thus appears to depend on competing signals produced by the tumor and surrounding tissue. Science , this issue p. 1029
- Published
- 2019
7. Comparison of the
- Author
-
Bram, Lesaffer, Elisabeth, Verboven, Leen, Van Huffel, Iván M, Moya, Leo A, van Grunsven, Isabelle A, Leclercq, Frédéric P, Lemaigre, and Georg, Halder
- Subjects
Keratin-19 ,Male ,Opn ,Integrases ,Gene Expression ,knockout ,Mice, Transgenic ,Cre ,Ck19 ,Recombinant Proteins ,Animals, Genetically Modified ,Mice ,Tamoxifen ,mouse liver ,lineage tracing ,Liver ,Technical Note ,Animals ,Cell Lineage ,Female ,Osteopontin ,Bile Ducts ,cholangiocytes ,Genetic Engineering ,bile duct cells - Abstract
Inducible cyclization recombinase (Cre) transgenic mouse strains are powerful tools for cell lineage tracing and tissue-specific knockout experiments. However, low efficiency or leaky expression can be important pitfalls. Here, we compared the efficiency and specificity of two commonly used cholangiocyte-specific Cre drivers, the Opn-iCreERT2 and Ck19-CreERT drivers, using a tdTomato reporter strain. We found that Opn-iCreERT2 triggered recombination of the tdTomato reporter in 99.9% of all cholangiocytes while Ck19-CreERT only had 32% recombination efficiency after tamoxifen injection. In the absence of tamoxifen, recombination was also induced in 2% of cholangiocytes for the Opn-iCreERT2 driver and in 13% for the Ck19-CreERT driver. For both drivers, Cre recombination was highly specific for cholangiocytes since recombination was rare in other liver cell types. Toxic liver injury ectopically activated Opn-iCreERT2 but not Ck19-CreERT expression in hepatocytes. However, ectopic recombination in hepatocytes could be avoided by applying a three-day long wash-out period between tamoxifen treatment and toxin injection. Therefore, the Opn-iCreERT2 driver is best suited for the generation of mutant bile ducts, while the Ck19-CreERT driver has near absolute specificity for bile duct cells and is therefore favorable for lineage tracing experiments.
- Published
- 2019
8. Comparison of the Opn-CreER and Ck19-CreER Drivers in Bile Ducts of Normal and Injured Mouse Livers
- Author
-
Leen Van Huffel, Georg Halder, Iván M. Moya, Isabelle Leclercq, Bram Lesaffer, Leo A. van Grunsven, Frédéric P. Lemaigre, Elisabeth Verboven, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/DDUV/LPAD - Liver and pancreas differentiation, UCL - SSS/IREC/GAEN - Pôle d'Hépato-gastro-entérologie, UCL - (SLuc) Service de gastro-entérologie, Basic (bio-) Medical Sciences, Translational Liver Cell Biology, and Liver Cell Biology
- Subjects
0301 basic medicine ,Genetically modified mouse ,Opn ,Mutant ,knockout ,Biology ,Ck19 ,03 medical and health sciences ,0302 clinical medicine ,mouse liver ,lineage tracing ,medicine ,Recombinase ,Ectopic recombination ,cholangiocytes ,lcsh:QH301-705.5 ,bile duct cells ,Liver injury ,Bile duct ,Liver cell ,Cre ,General Medicine ,medicine.disease ,Cell biology ,030104 developmental biology ,medicine.anatomical_structure ,lcsh:Biology (General) ,030211 gastroenterology & hepatology ,Tamoxifen ,medicine.drug - Abstract
Inducible cyclization recombinase (Cre) transgenic mouse strains are powerful tools for cell lineage tracing and tissue-specific knockout experiments. However, low efficiency or leaky expression can be important pitfalls. Here, we compared the efficiency and specificity of two commonly used cholangiocyte-specific Cre drivers, the Opn-iCreERT2 and Ck19-CreERT drivers, using a tdTomato reporter strain. We found that Opn-iCreERT2 triggered recombination of the tdTomato reporter in 99.9% of all cholangiocytes while Ck19-CreERT only had 32% recombination efficiency after tamoxifen injection. In the absence of tamoxifen, recombination was also induced in 2% of cholangiocytes for the Opn-iCreERT2 driver and in 13% for the Ck19-CreERT driver. For both drivers, Cre recombination was highly specific for cholangiocytes since recombination was rare in other liver cell types. Toxic liver injury ectopically activated Opn-iCreERT2 but not Ck19-CreERT expression in hepatocytes. However, ectopic recombination in hepatocytes could be avoided by applying a three-day long wash-out period between tamoxifen treatment and toxin injection. Therefore, the Opn-iCreERT2 driver is best suited for the generation of mutant bile ducts, while the Ck19-CreERT driver has near absolute specificity for bile duct cells and is therefore favorable for lineage tracing experiments.
- Published
- 2019
9. YAP and TAZ Heterogeneity in Primary Liver Cancer: An Analysis of Its Prognostic and Diagnostic Role
- Author
-
Diethard Monbaliu, Chris Verslype, Guy Rens, Ruchan Karaman, Van, Haele, M, Olivier Govaere, Georg Halder, J Snoeck, Iván M. Moya, Baki Topal, Tania Roskams, and Frederik Nevens
- Subjects
0301 basic medicine ,Male ,TAZ ,Carcinogenesis ,Cell ,Kaplan-Meier Estimate ,medicine.disease_cause ,Hepatic progenitor cells ,lcsh:Chemistry ,Cholangiocarcinoma ,0302 clinical medicine ,Cytosol ,Expression pattern ,Keratin ,Medicine ,HCC ,lcsh:QH301-705.5 ,Spectroscopy ,chemistry.chemical_classification ,cHCC-CCA ,Liver Neoplasms ,Intracellular Signaling Peptides and Proteins ,General Medicine ,Middle Aged ,Prognosis ,Computer Science Applications ,Keratin 19 ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Female ,YAP ,Primary liver cancer ,Signal Transduction ,Carcinoma, Hepatocellular ,Catalysis ,Article ,Inorganic Chemistry ,03 medical and health sciences ,Genetic Heterogeneity ,Carcinoma ,Biomarkers, Tumor ,Humans ,Physical and Theoretical Chemistry ,CCA ,Molecular Biology ,Adaptor Proteins, Signal Transducing ,Aged ,Proportional Hazards Models ,Retrospective Studies ,Cell Nucleus ,Keratin-19 ,Hippo signaling pathway ,business.industry ,Organic Chemistry ,YAP-Signaling Proteins ,medicine.disease ,Phosphoproteins ,digestive system diseases ,030104 developmental biology ,Ki-67 Antigen ,chemistry ,lcsh:Biology (General) ,lcsh:QD1-999 ,Bile Duct Neoplasms ,Transcriptional Coactivator with PDZ-Binding Motif Proteins ,Cancer research ,Trans-Activators ,business ,Transcription Factors - Abstract
Primary liver cancer comprises a diverse group of liver tumors. The heterogeneity of these tumors is seen as one of the obstacles to finding an effective therapy. The Hippo pathway, with its downstream transcriptional co-activator Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), has a decisive role in the carcinogenesis of primary liver cancer. Therefore, we examined the expression pattern of YAP and TAZ in 141 patients with hepatocellular carcinoma keratin 19 positive (HCC K19+), hepatocellular carcinoma keratin 19 negative (HCC K19&minus, ), combined hepatocellular&ndash, cholangiocarcinoma carcinoma (cHCC-CCA), or cholangiocarcinoma (CCA). All cHCC-CCA and CCA patients showed high expression levels for YAP and TAZ, while only some patients of the HCC group were positive. Notably, we found that a histoscore of both markers is useful in the challenging diagnosis of cHCC-CCA. In addition, positivity for YAP and TAZ was observed in the hepatocellular and cholangiocellular components of cHCC-CCA, which suggests a single cell origin in cHCC-CCA. Within the K19&minus, HCC group, our results demonstrate that the expression of YAP is a statistically significant predictor of poor prognosis when observed in the cytoplasm. Nuclear expression of TAZ is an even more specific and independent predictor of poor disease-free survival and overall survival of K19&minus, HCC patients. Our results thus identify different levels of YAP/TAZ expression in various liver cancers that can be used for diagnostics.
- Published
- 2019
10. Abstract A13: Yap activity in bile ducts, but not in hepatocytes, is required for normal liver regeneration
- Author
-
Georg Halder, Elisabeth Verboven, and Iván M. Moya
- Subjects
Liver injury ,Cancer Research ,Hippo signaling pathway ,Bile duct ,Chemistry ,Regeneration (biology) ,Cancer ,medicine.disease ,Liver regeneration ,medicine.anatomical_structure ,Oncology ,Apoptosis ,medicine ,Cancer research ,Progenitor cell ,Molecular Biology - Abstract
The Hippo-pathway effectors Yap/Taz are assumed to be master regulators of organ regeneration. In the mouse liver, loss of Yap indeed affects the regeneration potential of hepatocytes. However, we found that this is not due to a requirement for Yap in hepatocytes to drive proliferation and regeneration, but is rather due to non-cell autonomous effects of the bile duct defects that develop in the absence of Yap. Developmental deletion of Yap and Taz in liver progenitors, which develop into hepatocytes and bile epithelial cells (BECs), impaired liver regeneration after toxin-induced injury. However, hepatocyte-specific deletion of Yap/Taz in adult mice revealed that Yap/Taz are dispensable in hepatocytes for liver regeneration. In contrast, deletion of Yap/Taz in mature BECs recapitulated the liver regeneration defects that were observed after knockout in liver progenitor cells. Notably, loss of Yap/Taz in BECs impaired bile duct integrity over time, induced a cholestatic liver phenotype, and increased apoptosis in wild-type hepatocytes after toxic liver injury. Our data show that Yap and Taz are required to maintain bile duct integrity, which is essential to maintain the regenerative capacity of adult hepatocytes. Citation Format: Elisabeth Verboven, Ivan M. Moya, Georg Halder. Yap activity in bile ducts, but not in hepatocytes, is required for normal liver regeneration [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A13.
- Published
- 2020
11. Functionality based method for simultaneous isolation of rodent hepatic sinusoidal cells
- Author
-
Inge Mannaerts, Cristina Ionica Øie, L.A. van Grunsven, L. Stradiot, Iván M. Moya, Stefaan Verhulst, T. Roosens, Georg Halder, Liver Cell Biology, Faculty of Medicine and Pharmacy, Basic (bio-) Medical Sciences, and Translational Liver Cell Biology
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,medicine.drug_class ,Liver cytology ,IgG ,FACS ,KUPFFER CELLS ,Biophysics ,Bioengineering ,Cell Separation ,Biology ,Chronic liver disease ,Statistics, Nonparametric ,Rats, Sprague-Dawley ,Biomaterials ,03 medical and health sciences ,Mice ,0302 clinical medicine ,In vivo ,medicine ,Animals ,Liver sinusoidal endothelial cells ,Retinoid ,Analysis of Variance ,Mice, Inbred BALB C ,Liver cell ,Cell sorting ,medicine.disease ,Flow Cytometry ,Immunohistochemistry ,In vitro ,Coculture Techniques ,Cell biology ,Rats ,Mice, Inbred C57BL ,030104 developmental biology ,Liver ,Mechanics of Materials ,Hepatic stellate cell ,Hepatocytes ,Ceramics and Composites ,030211 gastroenterology & hepatology ,Scavenging ,hepatic stellate cells - Abstract
Chronic liver disease is the result of long term exposure to viruses or toxins such as alcohol, fat and drugs, and forms the basis for the development of liver fibrosis and primary liver cancer. In vitro and in vivo models are key to study the pathways involved in chronic liver disease and for the development of therapeutics. 3D co-culture systems are becoming the in vitro standard, which requires freshly isolated primary hepatic cells. We developed a novel isolation method to simultaneously isolate liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs) and hepatic stellate cells (HSCs). The method exploits the scavenging activity of LSECs, the phagocytic capacity of KCs and the retinoid content of HSCs in vivo to enable direct processing by fluorescence-activated cell sorting without additional antibody binding and washing steps. UFACS3, for UV-FACS-based isolation of 3 non-parenchymal liver cell types, yields functional and pure LSECs (98 ± 1%), KCs (98 ± 1%) and HSCs (97 ± 3%), with less hands-on time from healthy and diseased rodent livers. This novel approach allows a fast and effective combined isolation of sinusoidal cells for further analysis.
- Published
- 2017
12. Mask Is Required for the Activity of the Hippo Pathway Effector Yki/YAP
- Author
-
Chunyao Tao, Leticia Sansores-Garcia, Mardelle Atkins, Maria Shahmoradgoli, Georg Halder, Iván M. Moya, and Gordon B. Mills
- Subjects
Breast Neoplasms ,Protein Serine-Threonine Kinases ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,RNA interference ,Animals ,Drosophila Proteins ,Humans ,Transcription factor ,Adaptor Proteins, Signal Transducing ,Regulation of gene expression ,Hippo signaling pathway ,Agricultural and Biological Sciences(all) ,Biochemistry, Genetics and Molecular Biology(all) ,Effector ,fungi ,Intracellular Signaling Peptides and Proteins ,Nuclear Proteins ,RNA-Binding Proteins ,Signal transducing adaptor protein ,YAP-Signaling Proteins ,Phosphoproteins ,KH domain ,Cell biology ,DNA-Binding Proteins ,body regions ,HEK293 Cells ,Gene Expression Regulation ,Trans-Activators ,Drosophila ,Female ,RNA Interference ,Signal transduction ,General Agricultural and Biological Sciences ,Signal Transduction ,Transcription Factors - Abstract
SummaryThe Drosophila Yorkie (Yki) protein and its mammalian homolog Yes-associated protein (YAP) are potent growth promoters, and YAP overexpression is associated with multiple types of cancer [1, 2]. Yki and YAP are transcriptional coactivators and function as downstream effectors of the Hippo tumor suppressor pathway [1–4]. The regulation of Yki and YAP by the Hippo signaling pathway has been extensively investigated; however, how they regulate gene expression is poorly understood. To identify additional regulators of Yki activity, we performed a genome-wide RNAi screen in Drosophila S2 cells. In this screen, we identified the conserved protein Mask (Multiple ankyrin repeats single KH domain) as a novel promoter of Yki activity in vitro and validated this function in vivo in Drosophila. We found that Mask is required downstream of the Hippo pathway for Yki to induce target-gene expression and that Mask forms complexes with Yki. The human Mask homolog MASK1 complexes with YAP and is required for the full activity of YAP. Additionally, elevated MASK1 expression is associated with worsened outcomes for breast cancer patients. We conclude that Mask is a novel cofactor for Yki/YAP required for optimal Yki/YAP activity during development and oncogenesis.
- Published
- 2013
13. The Hippo pathway in cellular reprogramming and regeneration of different organs
- Author
-
Georg Halder and Iván M. Moya
- Subjects
0301 basic medicine ,animal structures ,Biology ,Protein Serine-Threonine Kinases ,Regenerative medicine ,03 medical and health sciences ,Neoplasms ,Animals ,Humans ,Regeneration ,Hippo signaling pathway ,Regeneration (biology) ,Stem Cells ,fungi ,Cell Biology ,Cellular Reprogramming ,Cell biology ,body regions ,030104 developmental biology ,Hippo signaling ,Organ Specificity ,Signal transduction ,Reprogramming ,Homeostasis ,Signal Transduction - Abstract
We have a limited ability to stimulate cells in damaged tissues to regenerate properly patterned and functional organs. Excitingly, however, recent work shows that experimental modulation of the Hippo pathway can promote the regeneration of several organs in mice. The Hippo pathway plays pivotal and specific roles in organ growth, cellular plasticity, and stem cell biology, which are all important for regeneration. In this review we survey and compare the effects of experimental manipulation of Hippo signaling in mouse on the development, homeostasis, and regeneration of the heart, liver, intestine, and other organs. We also discuss the potential of targeting the Hippo pathway as a therapeutic approach for regenerative medicine.
- Published
- 2016
14. Stalk Cell Phenotype Depends on Integration of Notch and Smad1/5 Signaling Cascades
- Author
-
An Zwijsen, Annick Francis, Danny Huylebroeck, Karen Beets, Elizabeth J. Robertson, Paulo N. G. Pereira, Elke Maas, Christine L. Mummery, Iván M. Moya, Ward Sents, and Lieve Umans
- Subjects
Inhibitor of Differentiation Protein 1 ,Smad5 Protein ,endocrine system ,animal structures ,Endothelium ,Notch signaling pathway ,Down-Regulation ,Neovascularization, Physiologic ,Cell Cycle Proteins ,Mice, Transgenic ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,Smad1 Protein ,Mice ,Serrate-Jagged Proteins ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,Humans ,HES1 ,Molecular Biology ,Cells, Cultured ,Adaptor Proteins, Signal Transducing ,Inhibitor of Differentiation Protein 2 ,Homeodomain Proteins ,Mice, Knockout ,Vascular Endothelial Growth Factor Receptor-1 ,Calcium-Binding Proteins ,Intracellular Signaling Peptides and Proteins ,Membrane Proteins ,Cell Biology ,Cell biology ,medicine.anatomical_structure ,Phenotype ,Notch proteins ,Hes3 signaling axis ,embryonic structures ,cardiovascular system ,Jagged-1 Protein ,Intercellular Signaling Peptides and Proteins ,Transcription Factor HES-1 ,Inhibitor of Differentiation Proteins ,Signal transduction ,Signal Transduction ,Developmental Biology - Abstract
Gradients of vascular endothelial growth factor (VEGF) induce single endothelial cells to become leading tip cells of emerging angiogenic sprouts. Tip cells then suppress tip-cell features in adjacent stalk cells via Dll4/Notch-mediated lateral inhibition. We report here that Smad1/Smad5-mediated BMP signaling synergizes with Notch signaling during selection of tip and stalk cells. Endothelium-specific inactivation of Smad1/Smad5 in mouse embryos results in impaired Dll4/Notch signaling and increased numbers of tip-cell-like cells at the expense of stalk cells. Smad1/5 downregulation in cultured endothelial cells reduced the expression of several target genes of Notch and of other stalk-cell-enriched transcripts (Hes1, Hey1, Jagged1, VEGFR1, and Id1-3). Moreover, Id proteins act as competence factors for stalk cells and form complexes with Hes1, which augment Hes1 levels in the endothelium. Our findings provide in vivo evidence for a regulatory loop between BMP/TGFβ-Smad1/5 and Notch signaling that orchestrates tip- versus stalk-cell selection and vessel plasticity. ispartof: DEVELOPMENTAL CELL vol:22 issue:3 pages:501-514 ispartof: location:United States status: published
- Published
- 2012
- Full Text
- View/download PDF
15. Few Smad proteins and many Smad-interacting proteins yield multiple functions and action modes in TGFβ/BMP signaling in vivo
- Author
-
Luk Cox, Kathleen Coddens, Silvia Cazzola, Abdelilah Ibrahimi, Andrea Conidi, Liesbeth Vermeire, An Zwijsen, Annick Francis, Lieve Umans, Elke Maas, Griet Verstappen, Iván M. Moya, Karen Beets, Camila V. Esguerra, Ruben Dries, Paulo N. G. Pereira, Flore Lesage, Mariya P. Dobreva, Danny Huylebroeck, F.M. Cornelis, Debruyn Joke, Roel Kroes, Veronique van den Berghe, Eve Seuntjens, Elke Stappers, Clara Collart, and Agata Stryjewska
- Subjects
Genetics ,biology ,Endocrinology, Diabetes and Metabolism ,Protein subunit ,Immunology ,Smad Proteins ,Cleavage and polyadenylation specificity factor ,SMAD ,Transforming growth factor beta ,Bone morphogenetic protein ,General Biochemistry, Genetics and Molecular Biology ,Cell biology ,Transforming Growth Factor beta ,Transcription (biology) ,Bone Morphogenetic Proteins ,biology.protein ,Animals ,Humans ,Immunology and Allergy ,Signal transduction ,Transcription factor ,Signal Transduction - Abstract
Signaling by the many ligands of the TGFβ family strongly converges towards only five receptor-activated, intracellular Smad proteins, which fall into two classes i.e. Smad2/3 and Smad1/5/8, respectively. These Smads bind to a surprisingly high number of Smad-interacting proteins (SIPs), many of which are transcription factors (TFs) that co-operate in Smad-controlled target gene transcription in a cell type and context specific manner. A combination of functional analyses in vivo as well as in cell cultures and biochemical studies has revealed the enormous versatility of the Smad proteins. Smads and their SIPs regulate diverse molecular and cellular processes and are also directly relevant to development and disease. In this survey, we selected appropriate examples on the BMP-Smads, with emphasis on Smad1 and Smad5, and on a number of SIPs, i.e. the CPSF subunit Smicl, Ttrap (Tdp2) and Sip1 (Zeb2, Zfhx1b) from our own research carried out in three different vertebrate models. ispartof: Cytokine & Growth Factor Reviews vol:22 issue:5 pages:287-300 ispartof: location:England status: published
- Published
- 2011
16. Differential regulation of the Hippo pathway by adherens junctions and apical-basal cell polarity modules
- Author
-
Fisun Hamaratoglu, Georg Halder, Iván M. Moya, Hillary K. Graves, Andrew B. Gladden, Chih Chao Yang, and Chunyao Tao
- Subjects
SCRIB ,animal structures ,Alpha catenin ,Biology ,Protein Serine-Threonine Kinases ,Real-Time Polymerase Chain Reaction ,Madin Darby Canine Kidney Cells ,Adherens junction ,Dogs ,Cell polarity ,Morphogenesis ,Animals ,Drosophila Proteins ,Humans ,Nuclear protein ,RNA, Small Interfering ,Crosses, Genetic ,DNA Primers ,Hippo signaling pathway ,Multidisciplinary ,Cadherin ,Tumor Suppressor Proteins ,fungi ,Intracellular Signaling Peptides and Proteins ,Cell Polarity ,Membrane Proteins ,Nuclear Proteins ,YAP-Signaling Proteins ,Adherens Junctions ,Biological Sciences ,Cadherins ,Cell biology ,body regions ,Imaginal disc ,Imaginal Discs ,Gene Knockdown Techniques ,Trans-Activators ,Drosophila ,RNA Interference ,Caco-2 Cells ,Cell Adhesion Molecules ,alpha Catenin ,Signal Transduction - Abstract
Adherens junctions (AJs) and cell polarity complexes are key players in the establishment and maintenance of apical-basal cell polarity. Loss of AJs or basolateral polarity components promotes tumor formation and metastasis. Recent studies in vertebrate models show that loss of AJs or loss of the basolateral component Scribble (Scrib) cause deregulation of the Hippo tumor suppressor pathway and hyperactivation of its downstream effectors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). However, whether AJs and Scrib act through the same or independent mechanisms to regulate Hippo pathway activity is not known. Here, we dissect how disruption of AJs or loss of basolateral components affect the activity of the Drosophila YAP homolog Yorkie (Yki) during imaginal disc development. Surprisingly, disruption of AJs and loss of basolateral proteins produced very different effects on Yki activity. Yki activity was cell-autonomously decreased but non-cell-autonomously elevated in tissues where the AJ components E-cadherin (E-cad) or α-catenin (α-cat) were knocked down. In contrast, scrib knockdown caused a predominantly cell-autonomous activation of Yki. Moreover, disruption of AJs or basolateral proteins had different effects on cell polarity and tissue size. Simultaneous knockdown of α-cat and scrib induced both cell-autonomous and non-cell-autonomous Yki activity. In mammalian cells, knockdown of E-cad or α-cat caused nuclear accumulation and activation of YAP without overt effects on Scrib localization and vice versa. Therefore, our results indicate the existence of multiple, genetically separable inputs from AJs and cell polarity complexes into Yki/YAP regulation.
- Published
- 2015
17. Novel Low-Cost and Efficient Method for the Isolation of Mouse Liver Sinusoidal Cells
- Author
-
Inge Mannaerts, Georg Halder, L.A. van Grunsven, L. Stradiot, Iván M. Moya, Basic (bio-) Medical Sciences, Liver Cell Biology, Faculty of Medicine and Pharmacy, and Translational Liver Cell Biology
- Subjects
Hepatology ,Isolation (health care) ,Chemistry ,Cell biology - Published
- 2016
18. YAP/TAZ Orchestrate VEGF Signaling during Developmental Angiogenesis
- Author
-
Georg Halder, Xiaohong Wang, Severino Urban, Tamás Fischer, Rakesh K. Jain, Carmen Ruiz de Almodovar, Laura Castro, Lars Riedemann, Frank Winkler, Aida Freire Valls, Massimilano Mazzone, Ying Shen, Iván M. Moya, Gergely Solecki, Géza Schermann, and Thomas Schmidt
- Subjects
TAZ ,Vascular Endothelial Growth Factor A ,0301 basic medicine ,Transcription, Genetic ,Angiogenesis ,Golgi Apparatus ,Cell Cycle Proteins ,angiogenesis ,Gene Knockout Techniques ,Mice ,chemistry.chemical_compound ,CNS vascularization ,Models ,Cell Movement ,Cytoskeleton ,Tumor ,Neovascularization, Pathologic ,Adaptor Proteins ,Brain ,VEGF ,Cell biology ,Vascular endothelial growth factor ,Actin Cytoskeleton ,Vascular endothelial growth factor A ,VEGFR2 ,YAP ,Signal transduction ,Transcription ,Signal Transduction ,Chromatin Immunoprecipitation ,hippo pathway ,Embryonic Development ,Neovascularization, Physiologic ,Biology ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,endothelial cells ,YAP/TAZ ,Adaptor Proteins, Signal Transducing ,Animals ,Animals, Newborn ,Cell Line, Tumor ,Cell Membrane ,Cell Nucleus ,Endothelial Cells ,Gene Deletion ,Gene Silencing ,Phosphoproteins ,Trans-Activators ,Vascular Endothelial Growth Factor Receptor-2 ,YAP-Signaling Proteins ,03 medical and health sciences ,Genetic ,Physiologic ,Molecular Biology ,Neovascularization ,Pathologic ,Hippo signaling pathway ,Signal Transducing ,Kinase insert domain receptor ,Cell Biology ,Newborn ,Biological ,Actin cytoskeleton ,030104 developmental biology ,chemistry ,Developmental Biology - Abstract
Vascular endothelial growth factor (VEGF) is a major driver of blood vessel formation. However, the signal transduction pathways culminating in the biological consequences of VEGF signaling are only partially understood. Here, we show that the Hippo pathway effectors YAP and TAZ work as crucial signal transducers to mediate VEGF-VEGFR2 signaling during angiogenesis. We demonstrate that YAP/TAZ are essential for vascular development as endothelium-specific deletion of YAP/TAZ leads to impaired vascularization and embryonic lethality. Mechanistically, we show that VEGF activates YAP/TAZ via its effects on actin cytoskeleton and that activated YAP/TAZ induce a transcriptional program to further control cytoskeleton dynamics and thus establish a feedforward loop that ensures a proper angiogenic response. Lack of YAP/TAZ also results in altered cellular distribution of VEGFR2 due to trafficking defects from the Golgi apparatus to the plasma membrane. Altogether, our study identifies YAP/TAZ as central mediators of VEGF signaling and therefore as important regulators of angiogenesis.
- Published
- 2017
19. Robustness in angiogenesis: notch and BMP shaping waves
- Author
-
Lieve Umans, Danny Huylebroeck, Karen Beets, An Zwijsen, and Iván M. Moya
- Subjects
Angiogenesis ,Cell ,Neovascularization, Physiologic ,Smad Proteins ,Biology ,Bone morphogenetic protein ,Neovascularization ,Lateral inhibition ,Genetics ,medicine ,Basic Helix-Loop-Helix Transcription Factors ,Animals ,Humans ,Regulation of gene expression ,Receptors, Notch ,Effector ,Anatomy ,Cell biology ,medicine.anatomical_structure ,Gene Expression Regulation ,Bone Morphogenetic Proteins ,cardiovascular system ,Blood Vessels ,Intercellular Signaling Peptides and Proteins ,Signal transduction ,medicine.symptom ,Protein Binding ,Signal Transduction - Abstract
Vascular patterning involves sprouting of blood vessels, which is governed by orchestrated communication between cells in the surrounding tissue and endothelial cells (ECs) lining the blood vessels. Single ECs are selected for sprouting by hypoxia-induced stimuli and become the 'tip' or leader cell that guides new sprouts. The 'stalk' or trailing ECs proliferate for tube extension and lumenize the nascent vessel. Stalk and tip cells can dynamically switch their identities during this process in a Notch-dependent manner. Here, we review recent studies showing that bone morphogenetic protein (BMP) signaling coregulates Notch target genes in ECs. In particular, we focus on how Delta-like ligand 4 (DLL4)-Notch and BMP effector interplay may drive nonsynchronized oscillatory gene expression in ECs essential for setting sharp tip-stalk cell boundaries while sustaining a dynamic pool of nonsprouting ECs. Deeper knowledge about the coregulation of vessel plasticity in different vascular beds may result in refinement of anti-angiogenesis and vessel normalization therapies. ispartof: Trends in Genetics vol:29 issue:3 pages:140-9 ispartof: location:England status: published
- Published
- 2012
20. Antagonism of Nodal signaling by BMP/Smad5 prevents ectopic primitive streak formation in the mouse amnion
- Author
-
Mariya P. Dobreva, F.M. Cornelis, An Zwijsen, Lieve Umans, Danny Huylebroeck, Paulo N. G. Pereira, Catherine M. Verfaillie, Susana M. Chuva de Sousa Lopes, Anne Camus, Iván M. Moya, Elke Maas, Department of Molecular and Developmental Genetics (VIB11), Flanders institute of biotechnology, Laboratory of Molecular Biology (CELGEN), Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Interdepartmental Stem Cell Institute Leuven, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department of Anatomy and Embryology, Leiden University Medical Center, Leiden University Medical Center (LUMC), Ciência e Tecnologia (FCT) [SFRH/BD/15901/2005] (GABBA program class of 2005), FCT, and Interuniversity Attraction Poles Program IUAP-6, FWO-V (G.0382.07), OT-09/053 and GOA-11/012, he KU Leuven Research Council
- Subjects
Mouse ,MESH: Bone Morphogenetic Proteins ,Nodal signaling ,Nodal ,Mice ,0302 clinical medicine ,MESH: Pregnancy ,Pregnancy ,MESH: Reverse Transcriptase Polymerase Chain Reaction ,MESH: Animals ,[SDV.BDD]Life Sciences [q-bio]/Development Biology ,In Situ Hybridization ,Smad ,0303 health sciences ,Amnion ,Primitive streak formation ,Primitive streak ,Reverse Transcriptase Polymerase Chain Reaction ,Immunohistochemistry ,Cell biology ,medicine.anatomical_structure ,Bone Morphogenetic Proteins ,embryonic structures ,Female ,Smad5 Protein ,medicine.medical_specialty ,animal structures ,Nodal Protein ,Blotting, Western ,Biology ,Bone morphogenetic protein ,Cell Line ,03 medical and health sciences ,MESH: Smad5 Protein ,MESH: In Situ Hybridization ,Internal medicine ,medicine ,Animals ,Humans ,Immunoprecipitation ,MESH: Blotting, Western ,MESH: Amnion ,Molecular Biology ,MESH: Mice ,MESH: Nodal Protein ,030304 developmental biology ,MESH: Humans ,MESH: Immunoprecipitation ,Bone Morphogenetic Protein ,MESH: Immunohistochemistry ,Embryonic stem cell ,MESH: Cell Line ,MESH: Primitive Streak ,Endocrinology ,Epiblast ,NODAL ,MESH: Female ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
The strength and spatiotemporal activity of Nodal signaling is tightly controlled in early implantation mouse embryos, including by autoregulation and feedback loops, and involves secreted and intracellular antagonists. These control mechanisms, which are established at the extra-embryonic/embryonic interfaces, are essential for anterior-posterior patterning of the epiblast and correct positioning of the primitive streak. Formation of an ectopic primitive streak, or streak expansion, has previously been reported in mutants lacking antagonists that target Nodal signaling. Here, we demonstrate that loss-of-function of a major bone morphogenetic protein (BMP) effector, Smad5, results in formation of an ectopic primitive streak-like structure in mutant amnion accompanied by ectopic Nodal expression. This suggests that BMP/Smad5 signaling contributes to negative regulation of Nodal. In cultured cells, we find that BMP-activated Smad5 antagonizes Nodal signaling by interfering with the Nodal-Smad2/4-Foxh1 autoregulatory pathway through the formation of an unusual BMP4-induced Smad complex containing Smad2 and Smad5. Quantitative expression analysis supports that ectopic Nodal expression in the Smad5 mutant amnion is induced by the Nodal autoregulatory loop and a slow positive-feedback loop. The latter involves BMP4 signaling and also induction of ectopic Wnt3. Ectopic activation of these Nodal feedback loops in the Smad5 mutant amnion results in the eventual formation of an ectopic primitive streak-like structure. We conclude that antagonism of Nodal signaling by BMP/Smad5 signaling prevents primitive streak formation in the amnion of normal mouse embryos. ispartof: Development vol:139 issue:18 pages:3343-3354 ispartof: location:England status: published
- Published
- 2012
21. Discovering the Hippo pathway protein-protein interactome
- Author
-
Georg Halder and Iván M. Moya
- Subjects
endocrine system ,Protein Serine-Threonine Kinases ,Biology ,Interactome ,RNA interference ,Animals ,Humans ,Hippo Signaling Pathway ,Protein Interaction Maps ,Phosphorylation ,Nuclear protein ,Molecular Biology ,Transcription factor ,Cytoskeleton ,Hippo signaling pathway ,Tight Junction Proteins ,Regeneration (biology) ,Nuclear Proteins ,Cell Biology ,Research Highlight ,Cell biology ,Transport protein ,Protein Transport ,Drosophila ,RNA Interference ,Signal transduction ,Signal Transduction ,Transcription Factors - Abstract
The Hippo pathway is a signal transduction pathway that regulates organ growth, stem cell biology, regeneration and cancer. Three recent proteomic studies with Hippo pathway components uncovered extensive networks of interacting proteins revealing novel connections to cell-cell junctions, regulation by vesicle trafficking, and phosphorylation-dependent remodeling of the interactome, and provide a rich landscape of novel interactors ripe for mechanistic studies.
- Published
- 2014
22. A comparative analysis of frog early development
- Author
-
Shinji Yamamoto, Natalia Sáenz-Ponce, Masanori Taira, Ingrid Alarcón, Michael Venegas-Ferrín, Paola C. Montenegro-Larrea, Norihiro Sudou, Iván M. Moya, Eugenia M. del Pino, and Andrés Romero-Carvajal
- Subjects
animal structures ,Embryo, Nonmammalian ,Engystomops randi ,Dorsal Lip ,Notochord ,Nervous System ,Gastrotheca riobambae ,Xenopus laevis ,medicine ,Animals ,Engystomops coloradorum ,Dorsal convergence ,Ovum ,Homeodomain Proteins ,Multidisciplinary ,biology ,Anatomy ,Gastrula ,Biological Sciences ,biology.organism_classification ,Cell biology ,Gastrulation ,medicine.anatomical_structure ,Somites ,Fertilization ,embryonic structures ,Anura ,Archenteron - Abstract
The current understanding of Xenopus laevis development provides a comparative background for the analysis of frog developmental modes. Our analysis of development in various frogs reveals that the mode of gastrulation is associated with developmental rate and is unrelated to egg size. In the gastrula of the rapidly developing embryos of the foam-nesting frogs Engystomops coloradorum and Engystomops randi , archenteron and notochord elongation overlapped with involution at the blastopore lip, as in X. laevis embryos. In embryos of dendrobatid frogs and in the frog without tadpoles Eleutherodactylus coqui , which develop somewhat more slowly than X. laevis , involution and archenteron elongation concomitantly occurred during gastrulation; whereas elongation of the notochord and, therefore, dorsal convergence and extension, occurred in the postgastrula. In contrast, in the slow developing embryos of the marsupial frog Gastrotheca riobambae , only involution occurred during gastrulation. The processes of archenteron and notochord elongation and convergence and extension were postgastrulation events. We produced an Ab against the homeodomain protein Lim1 from X. laevis as a tool for the comparative analysis of development. By the expression of Lim1, we were able to identify the dorsal side of the G. riobambae early gastrula, which otherwise was difficult to detect. Moreover, the Lim1 expression in the dorsal lip of the blastopore and notochord differed among the studied frogs, indicating variation in the timing of developmental events. The variation encountered gives evidence of the modular character of frog gastrulation.
- Published
- 2007
23. 13-P039 Endothelial specific Smad1 and Smad5 deficiency reveals a crutial role of BMP Smads in angiogenesis and lymphangiogenesis
- Author
-
An Zwijsen, Danny Huylebroeck, Ward Sents, Elke Maas, Lieve Umans, and Iván M. Moya
- Subjects
Embryology ,fluids and secretions ,Angiogenesis ,Cancer research ,food and beverages ,Biology ,Developmental Biology ,Lymphangiogenesis - Published
- 2009
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.