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12 results on '"MESH: Erythropoiesis"'

1. Comprehensive phenotyping of erythropoiesis in human bone marrow: Evaluation of normal and ineffective erythropoiesis

Author

Sandrina Kinet, Azra Raza, Lionel Blanc, Naomi Taylor, Erjing Gao, Abdullah Mahmood Ali, Hongxia Yan, Anupama Narla, Julien Papoin, John Hale, Narla Mohandas, Patrick G. Gallagher, Joseph M. Lane, Christopher D. Hillyer, New York Blood Center, Columbia University [New York], Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, The Feinstein Institute for Medical Research, Stanford University School of Medicine [CA, USA], Hospital for Special Surgery, Department of Linguistics, University of Georgia, Athens, GA 30602, USA, Hematopoïèse et Immunothérapie, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Pediatric Oncology Branch, National Institutes of Health - NIH-Center for Cancer Research - CCR-National Cancer Institute - NCI, Yale University School of Medicine, and Columbia University Irving Medical Center (CUIMC)

Subjects
Ineffective erythropoiesis, MESH: Immunophenotyping, [SDV]Life Sciences [q-bio], Population, CD34, Antigens, CD34, Bone Marrow Cells, MESH: Flow Cytometry, Stem cell factor, Biology, medicine.disease_cause, Article, Immunophenotyping, 03 medical and health sciences, 0302 clinical medicine, Erythroid Cells, Antigens, CD, hemic and lymphatic diseases, MESH: Erythroid Precursor Cells, medicine, Humans, Erythropoiesis, education, MESH: Antigens, CD, Cells, Cultured, Progenitor, Erythroid Precursor Cells, education.field_of_study, MESH: Humans, MESH: Bone Marrow Cells, MESH: Erythropoiesis, Endoglin, MESH: Antigens, CD34, Hematology, MESH: Erythroid Cells, Flow Cytometry, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Bone marrow, MESH: Endoglin, MESH: Cells, Cultured, 030215 immunology
Abstract

International audience; Identification of stage-specific erythroid cells is critical for studies of normal and disordered human erythropoiesis. While immunophenotypic strategies have previously been developed to identify cells at each stage of terminal erythroid differentiation, erythroid progenitors are currently defined very broadly. Refined strategies to identify and characterize BFU-E and CFU-E subsets are critically needed. To address this unmet need, a flow cytometry-based technique was developed that combines the established surface markers CD34 and CD36 with CD117, CD71, and CD105. This combination allowed for the separation of erythroid progenitor cells into four discrete populations along a continuum of progressive maturation, with increasing cell size and decreasing nuclear/cytoplasmic ratio, proliferative capacity and stem cell factor responsiveness. This strategy was validated in uncultured, primary erythroid cells isolated from bone marrow of healthy individuals. Functional colony assays of these progenitor populations revealed enrichment of BFU-E only in the earliest population, transitioning to cells yielding BFU-E and CFU-E, then CFU-E only. Utilizing CD34/CD105 and GPA/CD105 profiles, all four progenitor stages and all five stages of terminal erythroid differentiation could be identified. Applying this immunophenotyping strategy to primary bone marrow cells from patients with myelodysplastic syndrome, identified defects in erythroid progenitors and in terminal erythroid differentiation. This novel immunophenotyping technique will be a valuable tool for studies of normal and perturbed human erythropoiesis. It will allow for the discovery of stage-specific molecular and functional insights into normal erythropoiesis as well as for identification and characterization of stage-specific defects in inherited and acquired disorders of erythropoiesis.

Published
2021

2. Downregulation of Mitochondrial TSPO Inhibits Mitophagy and Reduces Enucleation During Human Terminal Erythropoiesis

Author

Naomi Taylor, Claude Hattab, Suella Martino, Mariano A. Ostuni, Sophie D. Lefevre, Martina Moras, Pedro Gonzalez-Menendez, Jérôme Larghero, Sandrina Kinet, Caroline Le Van Kim, KARLI, Mélanie, Biologie Intégrée du Globule Rouge (BIGR (UMR_S_1134 / U1134)), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université Paris Cité (UPCité), Institut National de la Transfusion Sanguine [Paris] (INTS), Laboratoire d'Excellence : Biogenèse et pathologies du globule rouge (Labex Gr-Ex), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Hematopoïèse et Immunothérapie, Institut de Génétique Moléculaire de Montpellier (IGMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CIC - Biotherapie - Saint Louis ((CIC-BT 301)), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Transfusion Sanguine [Paris] (INTS)-Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pointe-à-Pitre/Abymes [Guadeloupe] -Université des Antilles (UA)-Université de Paris (UP), Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), and Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)

Subjects
Mitochondrion, MESH: Benzodiazepinones, MESH: Down-Regulation, lcsh:Chemistry, 0302 clinical medicine, MESH: RNA, Small Interfering, Mitophagy, Erythropoiesis, RNA, Small Interfering, lcsh:QH301-705.5, Spectroscopy, 0303 health sciences, Benzodiazepinones, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, MESH: Kinetics, biology, VDAC, Chemistry, Cell Differentiation, General Medicine, Computer Science Applications, Cell biology, Mitochondria, Phenotype, MESH: Receptors, GABA, 030220 oncology & carcinogenesis, enucleation, MESH: Cell Differentiation, MESH: Cell Nucleus, Voltage-dependent anion channel, MESH: Mitochondria, MESH: Mitophagy, Down-Regulation, PINK1, MESH: Phenotype, Catalysis, Article, Inorganic Chemistry, 03 medical and health sciences, Downregulation and upregulation, Receptors, GABA, Erythroblast, Translocator protein, Humans, Physical and Theoretical Chemistry, Molecular Biology, 030304 developmental biology, Cell Nucleus, MESH: Humans, MESH: Erythropoiesis, Organic Chemistry, Kinetics, lcsh:Biology (General), lcsh:QD1-999, biology.protein, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, TSPO1
Abstract

International audience; Translocator protein (TSPO) and voltage dependent anion channels (VDAC) are two proteins forming a macromolecular complex in the outer mitochondrial membrane that is involved in pleiotropic functions. Specifically, these proteins were described to regulate the clearance of damaged mitochondria by selective mitophagy in non-erythroid immortalized cell lines. Although it is well established that erythroblast maturation in mammals depends on organelle clearance, less is known about mechanisms regulating this clearance throughout terminal erythropoiesis. Here, we studied the effect of TSPO1 downregulation and the action of Ro5-4864, a drug ligand known to bind to the TSPO/VDAC complex interface, in ex vivo human terminal erythropoiesis. We found that both treatments delay mitochondrial clearance, a process associated with reduced levels of the PINK1 protein, which is a key protein triggering canonical mitophagy. We also observed that TSPO1 downregulation blocks erythroblast maturation at the orthochromatic stage, decreases the enucleation rate, and increases cell death. Interestingly, TSPO1 downregulation does not modify reactive oxygen species (ROS) production nor intracellular adenosine triphosphate (ATP) levels. Ro5-4864 treatment recapitulates these phenotypes, strongly suggesting an active role of the TSPO/VDAC complex in selective mitophagy throughout human erythropoiesis. The present study links the function of the TSPO/VDAC complex to the PINK1/Parkin-dependent mitophagy induction during terminal erythropoiesis, leading to the proper completion of erythroid maturation.

Published
2020

3. Sex Determination in Malaria Parasites

Author

Paul T. Brey, Richard Paul, Tim Coulson, Anna Raibaud, Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris] (IP), Zoological Society of London - ZSL (UNITED KINGDOM), and Biochimie et Biologie Moléculaire des Insectes

Subjects
MESH: Sex Determination Processes, Male, Plasmodium, Erythrocytes, Reticulocytes, MESH: Reproduction, Plasmodium gallinaceum, MESH: Recombinant Proteins, Mice, Aedes, Parasite hosting, MESH: Animals, Erythropoiesis, media_common, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Multidisciplinary, biology, MESH: Erythrocytes, Reproduction, MESH: Chickens, MESH: Aedes, Recombinant Proteins, MESH: Malaria, Avian, Female, Sex ratio, Malaria, Avian, media_common.quotation_subject, MESH: Malaria, Zoology, MESH: Sex Ratio, Immune system, medicine, Animals, MESH: Erythropoietin, Sex Ratio, MESH: Mice, Erythropoietin, MESH: Plasmodium gallinaceum, Reproductive success, MESH: Plasmodium, MESH: Erythropoiesis, Sex Determination Processes, MESH: Reticulocytes, biology.organism_classification, medicine.disease, MESH: Male, Malaria, Immunology, Protozoa, MESH: Female, Chickens
Abstract

A century ago, W. G. MacCallum identified distinct male and female forms in malaria parasites of both birds and humans. Since then, scientists have been puzzled by the high female-to-male ratios of parasites inPlasmodiuminfections and by the mechanism of sex determination. The sex ratio of malaria parasites was shown to become progressively more male as conditions that allow motility and subsequent fertilization by the male parasites become adverse. This resulted from an increased immune response against male gametes, which coincides with intense host erythropoietic activity. Natural and artificial induction of erythropoiesis in vertebrate hosts provoked a shift toward male parasite production. This change in parasite sex ratio led to reduced reproductive success in the parasite, which suggests that sex determination is adaptive and is regulated by the hematologic state of the host.

Published
2000

4. Modelling Erythroblastic Islands: Using a Hybrid Model to Assess the Function of Central Macrophage

Author

Polina Kurbatova, Olivier Gandrillon, Nikolai Bessonov, Stephan Fischer, Fabien Crauste, Vitaly Volpert, COMputational BIology and data miNING (COMBINING), Laboratoire d'InfoRmatique en Image et Systèmes d'information (LIRIS), Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École Centrale de Lyon (ECL), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Université Lumière - Lyon 2 (UL2)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Multi-scale modelling of cell dynamics : application to hematopoiesis (DRACULA), Institut Camille Jordan [Villeurbanne] (ICJ), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institute of Mechanical Engineering Problems [St. Petersburg] (IPME), Russian Academy of Sciences [Moscow] (RAS), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), ANR-09-JCJC-0100,ProCell(2009), Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Université Lumière - Lyon 2 (UL2)-École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Camille Jordan (ICJ), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), and Institut Camille Jordan (ICJ)

Subjects
Erythroblasts, Macrophage, MESH: Feedback, Physiological, medicine.medical_treatment, Cell Communication, Quantitative Biology - Quantitative Methods, 0302 clinical medicine, Cell Behavior (q-bio.CB), Erythropoiesis, MESH: Erythroblasts, Quantitative Methods (q-bio.QM), Erythroblastic islands, Feedback, Physiological, 0303 health sciences, MESH: Bone Marrow Cells, Applied Mathematics, General Medicine, Cell biology, medicine.anatomical_structure, Biological Physics (physics.bio-ph), 030220 oncology & carcinogenesis, Modeling and Simulation, General Agricultural and Biological Sciences, Intracellular, Hybrid model, Statistics and Probability, FOS: Physical sciences, Bone Marrow Cells, Biology, Models, Biological, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, MESH: Cell Communication, medicine, Extracellular, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Physics - Biological Physics, Progenitor cell, 030304 developmental biology, MESH: Humans, General Immunology and Microbiology, Macrophages, Growth factor, MESH: Erythropoiesis, MESH: Models, Biological, MESH: Macrophages, Spindle apparatus, FOS: Biological sciences, Quantitative Biology - Cell Behavior, Bone marrow
Abstract

International audience; The production and regulation of red blood cells, erythropoiesis, occurs in the bone marrow where erythroid cells proliferate and differentiate within particular structures, called erythroblastic islands. A typical structure of these islands consists of a macrophage (white cell) surrounded by immature erythroid cells (progenitors), with more mature cells on the periphery of the island, ready to leave the bone marrow and enter the bloodstream. A hybrid model, coupling a continuous model (ordinary differential equations) describing intracellular regulation through competition of two key proteins, to a discrete spatial model describing cell-cell interactions, with growth factor diffusion in the medium described by a continuous model (partial differential equations), is proposed to investigate the role of the central macrophage in normal erythropoiesis. Intracellular competition of the two proteins leads the erythroid cell to either proliferation, differentiation, or death by apoptosis. This approach allows considering spatial aspects of erythropoiesis, involved for instance in the occurrence of cellular interactions or the access to external factors, as well as dynamics of intracellular and extracellular scales of this complex cellular process, accounting for stochasticity in cell cycle durations and orientation of the mitotic spindle. The analysis of the model shows a strong effect of the central macrophage on the stability of an erythroblastic island, when assuming the macrophage releases pro-survival cytokines. Even though it is not clear whether or not erythroblastic island stability must be required, investigation of the model concludes that stability improves responsiveness of the model, hence stressing out the potential relevance of the central macrophage in normal erythropoiesis.

Published
2011

5. Polymeric IgA1 controls erythroblast proliferation and accelerates erythropoiesis recovery in anemia

Author

Damien Grapton, Marie-Alexandra Alyanakian, Virginie Pascal, Michael Dussiot, Tomas Leanderson, Thiago Trovati Maciel, Olivier Hermine, Marc Benhamou, Séverine Coulon, Renato C. Monteiro, Patrick Mayeux, Kamel Djedaini, Zeliha Oruc, Julie Vandekerckhove, Saurabh Agarwal, Meetu Kaushik Tiwari, Michel Cogné, Ivan C. Moura, Bertrand Arnulf, Houda Tamouza, Geneviève Courtois, Aurélie Fricot, Pamella Huey Mei Wang, Yael Zermati, Jean-Antoine Ribeil, Céline Callens, Cytokines, hématopoïèse et réponse immune (CHRI), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hémostase, bio-ingénierie et remodelage cardiovasculaires (LBPC), Université Paris Diderot - Paris 7 (UPD7)-Université Paris 13 (UP13)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Galilée, Immunopathologie rénale, récepteurs et inflammation, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), Service d'hématologie biologique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Différenciation des cellules B, hémopathies, lymphoïdes et déficit de l'immunité humorale, Université Paris Diderot - Paris 7 (UPD7), Tolérance immunitaire et présentation antigénique: impact en auto-immunité et en transplantation, Institut Cochin (UMR_S567 / UMR 8104), Université de Limoges (UNILIM), Service d Hématologie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 ( UPD5 ), Cytokines, hématopoïèse et réponse immune ( CHRI ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Hémostase, bio-ingénierie et remodelage cardiovasculaires ( LBPC ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Galilée, Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations ( PMRIL ), Université de Limoges ( UNILIM ) -Génomique, Environnement, Immunité, Santé, Thérapeutique ( GEIST FR CNRS 3503 ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Université Paris Diderot - Paris 7 ( UPD7 ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université de Limoges ( UNILIM ), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5), and Slama, Catherine

Subjects
Ineffective erythropoiesis, MESH: Signal Transduction, MESH: Anemia, Erythroblasts, MESH: Mice, Inbred NOD, MESH: Anoxia, Mice, SCID, medicine.disease_cause, Mice, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Mice, Inbred NOD, hemic and lymphatic diseases, MESH : Cell Proliferation, MESH : Erythropoietin, [ SDV.IMM ] Life Sciences [q-bio]/Immunology, Erythropoiesis, MESH: Animals, MESH: Mice, SCID, MESH: Erythroblasts, Hypoxia, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, 0303 health sciences, Transferrin, Anemia, General Medicine, MESH : Transferrin, MESH : Mice, Transgenic, 3. Good health, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Mitogen-Activated Protein Kinases, MESH: Transferrin, medicine.drug, Signal Transduction, MESH: Cells, Cultured, MESH : Anoxia, MESH: Mice, Transgenic, MESH : Anemia, Transferrin receptor, Mice, Transgenic, MESH : Immunoglobulin A, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, MESH : Erythropoiesis, Erythroblast, MESH: Cell Proliferation, Receptors, Transferrin, MESH : Mice, MESH : Cells, Cultured, medicine, Animals, Humans, MESH : Receptors, Transferrin, MESH: Receptors, Transferrin, MESH: Erythropoietin, MESH: Immunoglobulin A, Erythropoietin, MESH: Mice, PI3K/AKT/mTOR pathway, 030304 developmental biology, Cell Proliferation, MESH : Signal Transduction, MESH: Humans, MESH : Mice, Inbred NOD, MESH : Humans, MESH: Erythropoiesis, MESH : Mitogen-Activated Protein Kinases, MESH : Phosphatidylinositol 3-Kinases, MESH : Erythroblasts, medicine.disease, MESH: Mitogen-Activated Protein Kinases, MESH : Mice, SCID, Immunoglobulin A, chemistry, MESH: Phosphatidylinositol 3-Kinases, Immunology, Cancer research, MESH : Animals
Abstract

International audience; Anemia because of insufficient production of and/or response to erythropoietin (Epo) is a major complication of chronic kidney disease and cancer. The mechanisms modulating the sensitivity of erythroblasts to Epo remain poorly understood. We show that, when cultured with Epo at suboptimal concentrations, the growth and clonogenic potential of erythroblasts was rescued by transferrin receptor 1 (TfR1)-bound polymeric IgA1 (pIgA1). Under homeostatic conditions, erythroblast numbers were increased in mice expressing human IgA1 compared to control mice. Hypoxic stress of these mice led to increased amounts of pIgA1 and erythroblast expansion. Expression of human IgA1 or treatment of wild-type mice with the TfR1 ligands pIgA1 or iron-loaded transferrin (Fe-Tf) accelerated recovery from acute anemia. TfR1 engagement by either pIgA1 or Fe-Tf increased cell sensitivity to Epo by inducing activation of mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. These cellular responses were mediated through the TfR1-internalization motif, YXXΦ. Our results show that pIgA1 and TfR1 are positive regulators of erythropoiesis in both physiological and pathological situations. Targeting this pathway may provide alternate approaches to the treatment of ineffective erythropoiesis and anemia.

Published
2011

6. Inducible Fli-1 gene deletion in adult mice modifies several myeloid lineage commitment decisions and accelerates proliferation arrest and terminal erythrocytic differentiation

Author

François Morlé, Michèle Weiss-Gayet, Joëlle Starck, Colette Gonnet, Vicat Jean-Michel, Boris Guyot, Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon

Subjects
Erythrocytes, Myeloid, Cellular differentiation, MESH: Flow Cytometry, Cell Separation, Biochemistry, MESH: Hematopoietic Stem Cells, Mice, 0302 clinical medicine, MESH: Reverse Transcriptase Polymerase Chain Reaction, Erythropoiesis, Myeloid Cells, MESH: Animals, 0303 health sciences, MESH: Proto-Oncogene Protein c-fli-1, Reverse Transcriptase Polymerase Chain Reaction, ETS transcription factor family, MESH: Erythrocytes, Cell Differentiation, Hematology, Flow Cytometry, Cell biology, MESH: Megakaryocytes, medicine.anatomical_structure, Myelopoiesis, Stem cell, Megakaryocytes, MESH: Cell Differentiation, MESH: Mice, Transgenic, Blotting, Western, Immunology, Mice, Transgenic, Biology, MESH: Cell Separation, 03 medical and health sciences, MESH: Cell Proliferation, medicine, Animals, MESH: Blotting, Western, Cell Lineage, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Progenitor cell, MESH: Mice, Cell Proliferation, 030304 developmental biology, Progenitor, Proto-Oncogene Protein c-fli-1, MESH: Erythropoiesis, Cell Biology, MESH: Cell Lineage, Hematopoietic Stem Cells, MESH: Myeloid Cells, MESH: Gene Deletion, Bone marrow, Gene Deletion, 030215 immunology
Abstract

This study investigated the role of the ETS transcription factor Fli-1 in adult myelopoiesis using new transgenic mice allowing inducible Fli-1 gene deletion. Fli-1 deletion in adult induced mild thrombocytopenia associated with a drastic decrease in large mature megakaryocytes number. Bone marrow bipotent megakaryocytic-erythrocytic progenitors (MEPs) increased by 50% without increase in erythrocytic and megakaryocytic common myeloid progenitor progeny, suggesting increased production from upstream stem cells. These MEPs were almost unable to generate pure colonies containing large mature megakaryocytes, but generated the same total number of colonies mainly identifiable as erythroid colonies containing a reduced number of more differentiated cells. Cytological and fluorescence-activated cell sorting analyses of MEP progeny in semisolid and liquid cultures confirmed the drastic decrease in large mature megakaryocytes but revealed a surprisingly modest (50%) reduction of CD41-positive cells indicating the persistence of a megakaryocytic commitment potential. Symmetrical increase and decrease of monocytic and granulocytic progenitors were also observed in the progeny of purified granulocytic-monocytic progenitors and common myeloid progenitors. In summary, this study indicates that Fli-1 controls several lineages commitment decisions at the stem cell, MEP, and granulocytic-monocytic progenitor levels, stimulates the proliferation of committed erythrocytic progenitors at the expense of their differentiation, and is a major regulator of late stages of megakaryocytic differentiation.

Published
2010

7. The MAPK ERK1 is a negative regulator of the adult steady-state splenic erythropoiesis

Author

Paule Opolon, Françoise Porteu, Jacques Pouysségur, L Cocault, Nathalie Saulnier, Gilles Pagès, Murielle Gaudry, Denis Clay, Michèle Souyri, Soizic Guihard, Vectorologie et transfert de gènes (VTG / UMR8121), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)

Subjects
MESH: Signal Transduction, MESH: Anemia, MESH: Spleen, MESH: Bone Morphogenetic Protein 4, Apoptosis, MESH: Flow Cytometry, Bone Morphogenetic Protein 4, Biochemistry, Mice, 0302 clinical medicine, hemic and lymphatic diseases, MESH: Oxidants, MESH: Reverse Transcriptase Polymerase Chain Reaction, Receptors, Erythropoietin, Erythropoiesis, MESH: Animals, MESH: Phenylhydrazines, MESH: Bone Marrow Transplantation, [SDV.BDD]Life Sciences [q-bio]/Development Biology, Bone Marrow Transplantation, Erythroid Precursor Cells, 0303 health sciences, education.field_of_study, Mitogen-Activated Protein Kinase 3, Reverse Transcriptase Polymerase Chain Reaction, Anemia, Hematology, Flow Cytometry, Oxidants, Phenylhydrazines, Haematopoiesis, medicine.anatomical_structure, Bone morphogenetic protein 4, 030220 oncology & carcinogenesis, Signal transduction, MESH: Mitogen-Activated Protein Kinase 3, Signal Transduction, medicine.drug, medicine.medical_specialty, Blotting, Western, Immunology, Population, Spleen, Biology, Colony-Forming Units Assay, 03 medical and health sciences, MESH: Mice, Inbred C57BL, Internal medicine, MESH: Erythroid Precursor Cells, medicine, Animals, MESH: Blotting, Western, MESH: Colony-Forming Units Assay, RNA, Messenger, MESH: Erythropoietin, MESH: Receptors, Erythropoietin, education, Erythropoietin, MESH: Mice, 030304 developmental biology, MESH: RNA, Messenger, MESH: Apoptosis, MESH: Erythropoiesis, Cell Biology, Mice, Inbred C57BL, Endocrinology, Bone marrow
Abstract

The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 1 (ERK1) and ERK2 are among the main signal transduction molecules, but little is known about their isoform-specific functions in vivo. We have examined the role of ERK1 in adult hematopoiesis with ERK1−/− mice. Loss of ERK1 resulted in an enhanced splenic erythropoiesis, characterized by an accumulation of erythroid progenitors in the spleen, without any effect on the other lineages or on bone marrow erythropoiesis. This result suggests that the ablation of ERK1 induces a splenic stress erythropoiesis phenotype. However, the mice display no anemia. Deletion of ERK1 did not affect erythropoietin (EPO) serum levels or EPO/EPO receptor signaling and was not compensated by ERK2. Splenic stress erythropoiesis response has been shown to require bone morphogenetic protein 4 (BMP4)–dependent signaling in vivo and to rely on the expansion of a resident specialized population of erythroid progenitors, termed stress erythroid burst-forming units (BFU-Es). A great expansion of stress BFU-Es and increased levels of BMP4 mRNA were found in ERK1−/− spleens. The ERK1−/− phenotype can be transferred by bone marrow cells. These findings show that ERK1 controls a BMP4-dependent step, regulating the steady state of splenic erythropoiesis.

Published
2010

8. Mathematical study of feedback control roles and relevance in stress erythropoiesis

Author

Fabien Crauste, Vitaly Volpert, Ivan Demin, Olivier Gandrillon, Institut Camille Jordan [Villeurbanne] (ICJ), École Centrale de Lyon (ECL), Université de Lyon-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Multi-scale modelling of cell dynamics : application to hematopoiesis (DRACULA), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Novartis Pharma AG, Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Equipe 'Bases Moléculaires de l'Autorenouvellement et de ses Altérations' Université de Lyon, Université de Lyon, Institut Camille Jordan (ICJ), Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut Camille Jordan (ICJ), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS)-École Centrale de Lyon (ECL)

Subjects
MAPK/ERK pathway, Feedback control, medicine.medical_treatment, Bioinformatics, 01 natural sciences, Mice, hemic and lymphatic diseases, Erythropoiesis, MESH: Animals, 0303 health sciences, MESH: Feedback, Applied Mathematics, Growth Factor, General Medicine, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 010101 applied mathematics, Modeling and Simulation, Erythroid cell, Bistability, General Agricultural and Biological Sciences, Intracellular, medicine.drug, Statistics and Probability, Anaemia, Biology, Models, Biological, General Biochemistry, Genetics and Molecular Biology, Feedback, 03 medical and health sciences, Intracellular Regulatory Network, medicine, Animals, MESH: Erythropoietin, 0101 mathematics, Erythropoietin, Glucocorticoids, MESH: Mice, 030304 developmental biology, General Immunology and Microbiology, Growth factor, MESH: Erythropoiesis, MESH: Mathematics, MESH: Models, Biological, Apoptosis, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], MESH: Glucocorticoids, Neuroscience, Mathematics
Abstract

International audience; This work is devoted to mathematical modelling of erythropoiesis. We propose a new multi-scale model, in which we bring together erythroid progenitor dynamics and intracellular regulatory network that determines erythroid cell fate. All erythroid progenitors are divided into several sub-populations according to their maturity. Two intracellular proteins, Erk and Fas, are supposed to be determinant for regulation of self-renewal, differentiation and apoptosis. We consider two growth factors, erythropoietin and glucocorticoids, and describe their dynamics. Several feedback controls are introduced in the model. We carry out computer simulations of anaemia and compare the obtained results with available experimental data on induced anaemia in mice. The main objective of this work is to evaluate the roles of the feedback controls in order to provide more insights into the regulation of erythropoiesis. Feedback by Epo on apoptosis is shown to be determinant in the early stages of the response to anaemia, whereas regulation through intracellular regulatory network, based on Erk and Fas, appears to operate on a long-term scale.

Published
2010

9. Direct binding of pRb/E2F-2 to GATA-1 regulates maturation and terminal cell division during erythropoiesis

Author

Philippe Leboulch, Masayuki Yamamoto, Osamu Ohneda, Ritsuko Shimizu, Leila Maouche-Chretien, Sylvie Gisselbrecht, Zahra Kadri, Paul-Henri Romeo, Stany Chrétien, Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Commissariat à l'énergie atomique et aux énergies alternatives (CEA) - Université Paris-Saclay, Thérapie génique et contrôle de l'expansion cellulaire (UMR E007), Université Paris-Saclay - Commissariat à l'énergie atomique et aux énergies alternatives (CEA) - Université Paris-Sud - Paris 11 (UP11), Institut Cochin (UMR_S567 / UMR 8104), Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM) - Centre National de la Recherche Scientifique (CNRS), Department of Molecular and Developmental Biology, University of Tsukuba, Genetics Division, Brigham and Women's Hospital [Boston], This work was supported by ARC and INSERM (SG, P-HR, LM-C, SC), National Institutes of Health grant to PL, the Fondation LeJeune and the Fondation de France (ZK), a Contrat d'Interface International from INSERM (SC), and ERATO-JST and MEXT (RS, OO, MY)., Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Tsukuba = University of Tsukuba, and Autard, Delphine

Subjects
MESH : Molecular Sequence Data, Cell division, MESH : Transcription Factors, Cellular differentiation, MESH : NIH 3T3 Cells, Amino Acid Motifs, Cell Biology/Cell Growth and Division, MESH: Amino Acid Sequence, Biochemistry, Retinoblastoma Protein, MESH: Amino Acid Motifs, Mice, 0302 clinical medicine, E2F2 Transcription Factor, MESH: E2F2 Transcription Factor, MESH : Cell Proliferation, MESH: Animals, Erythropoiesis, GATA1 Transcription Factor, Biology (General), Nuclear protein, MESH: GATA1 Transcription Factor, 0303 health sciences, biology, General Neuroscience, MESH : Amino Acid Sequence, Retinoblastoma protein, Nuclear Proteins, MESH : Protein Binding, MESH: Transcription Factors, MESH : Cell Division, MESH : E2F2 Transcription Factor, 3. Good health, Cell biology, 030220 oncology & carcinogenesis, MESH: Cell Division, Cell Biology/Nuclear Structure and Function, biological phenomena, cell phenomena, and immunity, General Agricultural and Biological Sciences, Cell Division, Research Article, Protein Binding, MESH : Amino Acid Motifs, QH301-705.5, Cell Biology/Developmental Molecular Mechanisms, Molecular Sequence Data, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Erythroid Cells, MESH : Erythropoiesis, MESH: Cell Proliferation, MESH : Mice, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Protein Binding, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Amino Acid Sequence, E2F, MESH: Mice, Molecular Biology, Transcription factor, MESH : Erythroid Cells, Cell Proliferation, 030304 developmental biology, MESH: Molecular Sequence Data, MESH: Humans, General Immunology and Microbiology, Cell growth, MESH: Erythropoiesis, MESH : Humans, MESH : Nuclear Proteins, MESH: Retinoblastoma Protein, MESH: Erythroid Cells, Molecular biology, MESH : GATA1 Transcription Factor, NIH 3T3 Cells, biology.protein, MESH : Animals, MESH: Nuclear Proteins, MESH : Retinoblastoma Protein, MESH: NIH 3T3 Cells, Transcription Factors
Abstract

Cell differentiation is often coupled with cell cycle arrest. Here, we show that direct binding of the erythroid transcription factor GATA-1 to the retinoblastoma protein and the pRb/E2F transcription factor complex is critical for red blood cell formation., How cell proliferation subsides as cells terminally differentiate remains largely enigmatic, although this phenomenon is central to the existence of multicellular organisms. Here, we show that GATA-1, the master transcription factor of erythropoiesis, forms a tricomplex with the retinoblastoma protein (pRb) and E2F-2. This interaction requires a LXCXE motif that is evolutionary conserved among GATA-1 orthologs yet absent from the other GATA family members. GATA-1/pRb/E2F-2 complex formation stalls cell proliferation and steers erythroid precursors towards terminal differentiation. This process can be disrupted in vitro by FOG-1, which displaces pRb/E2F-2 from GATA-1. A GATA-1 mutant unable to bind pRb fails to inhibit cell proliferation and results in mouse embryonic lethality by anemia. These findings clarify the previously suspected cell-autonomous role of pRb during erythropoiesis and may provide a unifying molecular mechanism for several mouse phenotypes and human diseases associated with GATA-1 mutations., Author Summary Red blood cell production, or erythropoiesis, proceeds by a tight coupling of proliferation and differentiation. The earliest erythroid progenitor identifiable possesses remnant stem cell characteristics as it both self-renews and differentiates. Each progenitor gives rise to more than 10,000 cells, including secondary progenitors. Yet, during the next stage of differentiation, much of this renewal capability is lost, and terminal erythroid differentiation progresses in a stepwise manner through several stages separated by a single mitosis. The transcription factor GATA-1 is essential for erythroid differentiation because it induces the expression of all the known erythroid-specific genes. Here, we show that GATA-1 directly interacts with proteins that are central to the process of cell division: the retinoblastoma protein pRb and the transcription factor E2F. Specifically, E2F becomes inactivate after engaging in a GATA-1/pRb/E2F tricomplex. Another erythroid transcription factor, termed FOG-1, is able to displace pRb/E2F from this complex in vitro upon binding to GATA-1. We hypothesize that the liberated pRb/E2F can then be the target of subsequent regulation to ultimately release free E2F, which triggers cell division. The physiological role of this new pathway is evidenced by transgenic mouse experiments with GATA-1 mutants unable to bind pRb/E2F, which result in embryonic lethality by anemia.

Published
2009

10. [Diamond-Blackfan anemia reveals the dark side of ribosome biogenesis]

Author

Aguissa-Touré, Almass-Houd, Da Costa, Lydie, Leblanc, Thierry, Tchernia, Gil, Fribourg, Sébastien, Gleizes, Pierre-Emmanuel, Laboratoire de biologie moléculaire eucaryote (LBME), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Hematopoïese et cellules souches normales et pathologiques (U790), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), AP-HP, Service d'Hématologie Biologique, Hôpital Robert-Debré, Université Paris Diderot - Paris 7 (UPD7), California Institute of Technology (CALTECH), Service d'hématologie, immunologie biologiques et cytogénétique, Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, ARN : régulations naturelle et artificielle, Université Bordeaux Segalen - Bordeaux 2-Institut Européen de Chimie et de Biologie-Institut National de la Santé et de la Recherche Médicale (INSERM), and Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11)

Subjects
Ribosomal Proteins, MESH: Genetic Diseases, Inborn, MESH: Humans, MESH: Mutation, Organelle Biogenesis, MESH: Erythropoiesis, Genetic Diseases, Inborn, MESH: Ribosomal Proteins, MESH: Biogenesis, MESH: Anemia, Diamond-Blackfan, MESH: RNA, RNA, Ribosomal, Mutation, MESH: RNA, Ribosomal, Humans, RNA, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Erythropoiesis, MESH: Ribosomes, Ribosomes, Anemia, Diamond-Blackfan
Abstract

International audience; Diamond-Blackfan anemia (DBA), a rare congenital erythroblastopenia, has recently become a paradigm for a growing set of genetic diseases linked to mutations in genes encoding ribosomal proteins or factors involved in ribosome biogenesis. Recent studies of the structure and the function of ribosomal proteins affected in DBA indicate that their mutation in DBA primarily impacts ribosome biogenesis. Accordingly, cells from DBA patients display anomalies in the maturation of ribosomal RNAs. The explanation of this unexpected link between ribosome biogenesis, a ubiquitous process, and a disease mostly affecting erythroid differentiation may stem in part from the emerging concept of ribosomal stress response, a signaling pathway triggering cell cycle arrest in response to a defect in ribosome synthesis. Future studies of DBA and other diseases related to defects in ribosome biogenesis are likely to rapidly provide important insights into the regulatory mechanisms linking cell cycle progression to this major metabolic pathway.

Published
2009

11. Combinatorial regulation of novel erythroid gene expression in zebrafish

Author

Rebecca A. Wingert, Bernard Thisse, Christine Thisse, Leonard I. Zon, Jenna L. Galloway, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I, Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université Louis Pasteur - Strasbourg I, and Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Cancer Research, Embryo, Nonmammalian, Morpholino, 0302 clinical medicine, MESH: Oligonucleotides, Antisense, MESH: Reverse Transcriptase Polymerase Chain Reaction, Gene expression, MESH: Basic Helix-Loop-Helix Transcription Factors, MESH: Gene Expression Regulation, Developmental, Basic Helix-Loop-Helix Transcription Factors, Erythropoiesis, GATA1 Transcription Factor, MESH: Animals, Zebrafish, T-Cell Acute Lymphocytic Leukemia Protein 1, MESH: GATA1 Transcription Factor, 0303 health sciences, biology, Reverse Transcriptase Polymerase Chain Reaction, GATA2, Gene Expression Regulation, Developmental, GATA1, Hematology, MESH: Transcription Factors, GATA2 Transcription Factor, Haematopoiesis, Receptors, Purinergic P2Y, MESH: Kruppel-Like Transcription Factors, animal structures, Kruppel-Like Transcription Factors, MESH: Zebrafish Proteins, Article, 03 medical and health sciences, Erythroid Cells, Proto-Oncogene Proteins, Genetics, Animals, MESH: Receptors, Purinergic P2, MESH: Zebrafish, Molecular Biology, Gene, Transcription factor, 030304 developmental biology, Receptors, Purinergic P2, MESH: Erythropoiesis, MESH: Embryo, Nonmammalian, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Oligonucleotides, Antisense, Zebrafish Proteins, MESH: Erythroid Cells, biology.organism_classification, Molecular biology, MESH: Proto-Oncogene Proteins, MESH: GATA2 Transcription Factor, 030217 neurology & neurosurgery, Transcription Factors
Abstract

Objective The specification and differentiation of hematopoietic stem cells into red blood cells requires precise coordination by multiple transcription factors. Most genes important for erythroid maturation are regulated by the Gata family of DNA-binding proteins. Previously, we identified three novel genes kelch-repeat containing protein ( krcp ), kiaa0650 , and testhymin/glucocorticoid inducible transcript 1 ( glcci1 ) to be expressed in erythroid cells in a Gata-independent manner, and we sought to further understand how these transcripts are regulated during zebrafish hematopoiesis. Materials and Methods We employed a loss-of-function approach, using combinations of antisense morpholinos to hematopoietic transcription factors and assayed for changes in gene expression in zebrafish embryos. Results Upon examination of embryos deficient for Gata1, Gata2, Biklf, and/or Scl, we found distinct gene combinations were required for expression of the novel genes. While krcp expression was dependent upon Gata1 and Biklf, kiaa0650 expression was greatly reduced and glcci1 was maintained in Gata1/Gata2/Biklf-deficient embryos. As with the gata1 gene, kiaa0650 and krcp required Scl for blood expression. Although reduced, glcci1 was expressed in posterior blood precursors in the absence of Scl and Gata2. Conclusions This work identifies glcci1 as having Scl-independent expression in the posterior hematopoietic mesoderm, suggesting that its posterior expression is activated by factors upstream or parallel to Scl and Gata2. Additionally, these studies establish that blood gene expression programs are regulated by transcription factors acting in combination during erythroid maturation.

Published
2008

12. Loss of gata1 but not gata2 converts erythropoiesis to myelopoiesis in zebrafish embryos

Author

Bernard Thisse, Rebecca A. Wingert, Leonard I. Zon, Christine Thisse, Jenna L. Galloway, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Louis Pasteur - Strasbourg I

Subjects
MESH: Cell Death, MESH: Myelopoiesis, Embryo, Nonmammalian, Myeloid, MESH: Flow Cytometry, MESH: Microinjections, Animals, Genetically Modified, 0302 clinical medicine, hemic and lymphatic diseases, MESH: Gene Expression Regulation, Developmental, MESH: Erythroid Progenitor Cells, Erythropoiesis, GATA1 Transcription Factor, MESH: Animals, MESH: In Situ Nick-End Labeling, In Situ Hybridization, Zebrafish, MESH: GATA1 Transcription Factor, Erythroid Precursor Cells, Myelopoiesis, Genetics, 0303 health sciences, MESH: Erythroid-Specific DNA-Binding Factors, Cell Death, GATA2, Gene Expression Regulation, Developmental, Cell Differentiation, GATA1, MESH: Transcription Factors, Flow Cytometry, Immunohistochemistry, Cell biology, DNA-Binding Proteins, Haematopoiesis, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Erythroid-Specific DNA-Binding Factors, MESH: Cell Differentiation, Microinjections, MESH: Zebrafish Proteins, Biology, General Biochemistry, Genetics and Molecular Biology, MESH: Animals, Genetically Modified, 03 medical and health sciences, MESH: In Situ Hybridization, In Situ Nick-End Labeling, medicine, Animals, Progenitor cell, MESH: Zebrafish, Molecular Biology, Transcription factor, 030304 developmental biology, MESH: Embryo, MESH: Erythropoiesis, MESH: Immunohistochemistry, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Cell Biology, Zebrafish Proteins, MESH: DNA-Binding Proteins, Transcription Factors, Developmental Biology
Abstract

International audience; The differentiation of hematopoietic progenitors into erythroid or myeloid cell lineages is thought to depend upon relative levels of the transcription factors gata1 and pu.1. While loss-of-function analysis shows that gata1 is necessary for terminal erythroid differentiation, no study has demonstrated that loss of gata1 alters myeloid differentiation during ontogeny. Here we provide in vivo evidence that loss of Gata1, but not Gata2, transforms primitive blood precursors into myeloid cells, resulting in a massive expansion of granulocytic neutrophils and macrophages at the expense of red blood cells. In addition to this fate change, expression of many erythroid genes was found to be differentially dependent on Gata1 alone, on both Gata1 and Gata2, or independent of both Gata factors, suggesting that multiple pathways regulate erythroid gene expression. Our studies establish a transcriptional hierarchy of Gata factor dependence during hematopoiesis and demonstrate that gata1 plays an integral role in directing myelo-erythroid lineage fate decisions during embryogenesis.

Published
2005

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