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2. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia
- Author
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Floriane Fusil, Stany Chrétien, Riccardo Sgarra, Beatrix Gillet-Legrand, Françoise Bernaudin, Nabil Kabbara, Robert Girot, Philippe Leboulch, Laure Caccavelli, Maria Denaro, Frédéric Galactéros, Julian D. Down, Marina Cavazzana-Calvo, Emmanuel Payen, Kathleen M. Hehir, Leila Maouche-Chretien, Bernard Gourmel, Kenneth Cornetta, Frederick D. Bushman, Axel Polack, Alain Fischer, Patrick Aubourg, Salima Hacein-Bey-Abina, Gérard Socié, Jérôme Larghero, Karen A. Westerman, Gary P. Wang, Nathalie Cartier, Eliane Gluckman, Yves Beuzard, Arthur Bank, Ronald Dorazio, Troy Brady, Geert Jan Mulder, Resy Cavallesco, Olivier Negre, Bruno Dalle, Jean Soulier, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Clinical Investigation Center in Biotherapy, Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Genetix-France, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Microbiology, University of Pennsylvania [Philadelphia], Genetix Pharmaceuticals, Genetics Division, Boston, Brigham and Women's Hospital [Boston], Department of Life Sciences, Trieste, University of Trieste, Service d'hématologie pédiatrique, Hôpital intercommunal de Créteil, CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Medicine and Department of Genetics and Development, Columbia University [New York], Departments of Hematology, Université Paris Diderot - Paris 7 (UPD7), Institute of Hematology, Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'hématologie greffe [Saint-Louis], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medical and Molecular Genetics, Indiana University [Bloomington], Indiana University System-Indiana University System, 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), Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), CHU Tenon [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-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)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania, Università degli studi di Trieste = University of Trieste, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-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)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Cambridge, MA, Department of Biology, Paris, Université Paris Diderot - Paris 7 ( UPD7 ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux ( Inserm U745 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Mondor de Recherche Biomédicale ( IMRB ), Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10, Cavazzana Calvo, M., Payen, E., Negre, O., Wang, G., Hehir, K., Fusil, F., Down, J., Denaro, M., Brady, T., Westerman, K., Cavallesco, R., Gillet Legrand, B., Caccavelli, L., Sgarra, Riccardo, Maouche Chrétien, L., Bernaudin, F., Girot, R., Dorazio, R., Mulder, G. J., Polack, A., Bank, A., Soulier, J., Larghero, J., Kabbara, N., Dalle, B., Gourmel, B., Socie, G., Chrétien, S., Cartier, N., Aubourg, P., Fischer, A., Cornetta, K., Galacteros, F., Beuzard, Y., Gluckman, E., Bushman, F., Hacein Bey Abina, S., and Leboulch, P.
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Male ,Transcriptional Activation ,Time Factors ,Adolescent ,Genetic enhancement ,Genetic Vectors ,Gene Expression ,Bone Marrow Cells ,beta-Globins ,Gene Terapy HMGA2 ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,Southeast asian ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,medicine ,Homeostasis ,Humans ,Blood Transfusion ,RNA, Messenger ,Progenitor cell ,030304 developmental biology ,0303 health sciences ,Blood Cells ,Multidisciplinary ,[ SDV.BC ] Life Sciences [q-bio]/Cellular Biology ,HMGA2 Protein ,Lentivirus ,beta-Thalassemia ,Genetic transfer ,Beta thalassemia ,Genetic Therapy ,medicine.disease ,Clone Cells ,3. Good health ,Transplantation ,MicroRNAs ,Haematopoiesis ,Organ Specificity ,Child, Preschool ,030220 oncology & carcinogenesis ,Immunology ,Stem cell - Abstract
Blood disorders caused by abnormal β-globin — β-thalassaemia and sickle cell disease — are the most prevalent inherited disorders worldwide, with patients often remaining dependent on blood transfusions throughout their lives. So a report of the successful use of gene therapy in a case of severe β-thalassaemia — using a lentiviral vector expressing the β-globin gene — is an eagerly awaited event. More than two years after gene transfer, the adult male patient has been transfusion-independent for 21 months. The therapeutic benefit seems to result from a dominant, myeloid-biased cell clone that may remain benign, although it could yet develop into leukaemia — a reminder that gene therapy is still at an early stage. Disorders caused by abnormal β-globin, such as β-thalassaemia, are the most prevalent inherited disorders worldwide. For treatment, many patients are dependent on blood transfusions; thus far the only cure has involved matched transplantation of haematopoietic stem cells. Here it is shown that lentiviral β-globin gene transfer can be an effective substitute for regular transfusions in a patient with severe β-thalassaemia. The β-haemoglobinopathies are the most prevalent inherited disorders worldwide. Gene therapy of β-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells. Compound βE/β0-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas1,2. The βE-globin allele bears a point mutation that causes alternative splicing. The abnormally spliced form is non-coding, whereas the correctly spliced messenger RNA expresses a mutated βE-globin with partial instability1,2. When this is compounded with a non-functional β0 allele, a profound decrease in β-globin synthesis results, and approximately half of βE/β0-thalassaemia patients are transfusion-dependent1,2. The only available curative therapy is allogeneic haematopoietic stem cell transplantation, although most patients do not have a human-leukocyte-antigen-matched, geno-identical donor, and those who do still risk rejection or graft-versus-host disease. Here we show that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe βE/β0-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months. Blood haemoglobin is maintained between 9 and 10 g dl−1, of which one-third contains vector-encoded β-globin. Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs. The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells.
- Published
- 2010
- Full Text
- View/download PDF
3. Pax6- and Six3-mediated induction of lens cell fate in mouse and human ES cells.
- Author
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Anchan RM, Lachke SA, Gerami-Naini B, Lindsey J, Ng N, Naber C, Nickerson M, Cavallesco R, Rowan S, Eaton JL, Xi Q, and Maas RL
- Subjects
- Animals, Blotting, Western, Cell Differentiation, Cell Proliferation, Cells, Cultured, Embryonic Stem Cells cytology, Eye Proteins genetics, Homeodomain Proteins genetics, Humans, Lens, Crystalline cytology, Mice, Nerve Tissue Proteins genetics, PAX6 Transcription Factor, Paired Box Transcription Factors genetics, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Repressor Proteins genetics, Reverse Transcriptase Polymerase Chain Reaction, Homeobox Protein SIX3, Embryonic Stem Cells physiology, Eye Proteins metabolism, Gene Expression Regulation, Developmental, Homeodomain Proteins metabolism, Lens, Crystalline physiology, Nerve Tissue Proteins metabolism, Paired Box Transcription Factors metabolism, Repressor Proteins metabolism
- Abstract
Embryonic stem (ES) cells provide a potentially useful in vitro model for the study of in vivo tissue differentiation. We used mouse and human ES cells to investigate whether the lens regulatory genes Pax6 and Six3 could induce lens cell fate in vitro. To help assess the onset of lens differentiation, we derived a new mES cell line (Pax6-GFP mES) that expresses a GFP reporter under the control of the Pax6 P0 promoter and lens ectoderm enhancer. Pax6 or Six3 expression vectors were introduced into mES or hES cells by transfection or lentiviral infection and the differentiating ES cells analyzed for lens marker expression. Transfection of mES cells with Pax6 or Six3 but not with other genes induced the expression of lens cell markers and up-regulated GFP reporter expression in Pax6-GFP mES cells by 3 days post-transfection. By 7 days post-transfection, mES cell cultures exhibited a>10-fold increase over controls in the number of colonies expressing γA-crystallin, a lens fiber cell differentiation marker. RT-PCR and immunostaining revealed induction of additional lens epithelial or fiber cell differentiation markers including Foxe3, Prox1, α- and β-crystallins, and Tdrd7. Moreover, γA-crystallin- or Prox1-expressing lentoid bodies formed by 30 days in culture. In hES cells, Pax6 or Six3 lentiviral vectors also induced lens marker expression. mES cells that express lens markers reside close to but are distinct from the Pax6 or Six3 transduced cells, suggesting that the latter induce nearby undifferentiated ES cells to adopt a lens fate by non-cell autonomous mechanisms. In sum, we describe a novel mES cell GFP reporter line that is useful for monitoring induction of lens fate, and demonstrate that Pax6 or Six3 is sufficient to induce ES cells to adopt a lens fate, potentially via non-cell autonomous mechanisms. These findings should facilitate investigations of lens development.
- Published
- 2014
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4. Deficiency of the cytoskeletal protein SPECC1L leads to oblique facial clefting.
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Saadi I, Alkuraya FS, Gisselbrecht SS, Goessling W, Cavallesco R, Turbe-Doan A, Petrin AL, Harris J, Siddiqui U, Grix AW Jr, Hove HD, Leboulch P, Glover TW, Morton CC, Richieri-Costa A, Murray JC, Erickson RP, and Maas RL
- Subjects
- Actins genetics, Animals, Cell Adhesion, Cell Line, Cell Movement genetics, Cell Proliferation, Cleft Palate pathology, Craniofacial Dysostosis pathology, Drosophila genetics, Drosophila metabolism, Eye Abnormalities pathology, Female, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Humans, In Situ Hybridization, Male, Maxillofacial Abnormalities pathology, Microtubules genetics, Microtubules metabolism, Mutation, Phenotype, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Tubulin genetics, Wnt Proteins genetics, Wnt Proteins metabolism, Zebrafish genetics, Zebrafish metabolism, Cleft Palate genetics, Craniofacial Dysostosis genetics, Cytoskeletal Proteins deficiency, Eye Abnormalities genetics, Maxillofacial Abnormalities genetics, Phosphoproteins deficiency, Phosphoproteins genetics
- Abstract
Genetic mutations responsible for oblique facial clefts (ObFC), a unique class of facial malformations, are largely unknown. We show that loss-of-function mutations in SPECC1L are pathogenic for this human developmental disorder and that SPECC1L is a critical organizer of vertebrate facial morphogenesis. During murine embryogenesis, Specc1l is expressed in cell populations of the developing facial primordial, which proliferate and fuse to form the face. In zebrafish, knockdown of a SPECC1L homolog produces a faceless phenotype with loss of jaw and facial structures, and knockdown in Drosophila phenocopies mutants in the integrin signaling pathway that exhibit cell-migration and -adhesion defects. Furthermore, in mammalian cells, SPECC1L colocalizes with both tubulin and actin, and its deficiency results in defective actin-cytoskeleton reorganization, as well as abnormal cell adhesion and migration. Collectively, these data demonstrate that SPECC1L functions in actin-cytoskeleton reorganization and is required for proper facial morphogenesis., (Copyright © 2011 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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- 2011
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5. Mutations in the RNA granule component TDRD7 cause cataract and glaucoma.
- Author
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Lachke SA, Alkuraya FS, Kneeland SC, Ohn T, Aboukhalil A, Howell GR, Saadi I, Cavallesco R, Yue Y, Tsai AC, Nair KS, Cosma MI, Smith RS, Hodges E, Alfadhli SM, Al-Hajeri A, Shamseldin HE, Behbehani A, Hannon GJ, Bulyk ML, Drack AV, Anderson PJ, John SW, and Maas RL
- Subjects
- Animals, Cataract congenital, Cataract pathology, Cell Line, Chick Embryo, Crystallins genetics, Crystallins metabolism, Cytoplasmic Granules metabolism, Embryonic Development, Female, Gene Knockdown Techniques, Humans, Hypospadias genetics, Lens, Crystalline embryology, Male, Mice, Mutation, Organogenesis, Protein Biosynthesis, RNA-Binding Proteins genetics, RNA-Binding Proteins metabolism, Ribonucleoproteins genetics, Spermatogenesis genetics, Cataract genetics, Gene Expression Regulation, Developmental, Glaucoma genetics, Lens, Crystalline metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Ribonucleoproteins metabolism
- Abstract
The precise transcriptional regulation of gene expression is essential for vertebrate development, but the role of posttranscriptional regulatory mechanisms is less clear. Cytoplasmic RNA granules (RGs) function in the posttranscriptional control of gene expression, but the extent of RG involvement in organogenesis is unknown. We describe two human cases of pediatric cataract with loss-of-function mutations in TDRD7 and demonstrate that Tdrd7 nullizygosity in mouse causes cataracts, as well as glaucoma and an arrest in spermatogenesis. TDRD7 is a Tudor domain RNA binding protein that is expressed in lens fiber cells in distinct TDRD7-RGs that interact with STAU1-ribonucleoproteins (RNPs). TDRD7 coimmunoprecipitates with specific lens messenger RNAs (mRNAs) and is required for the posttranscriptional control of mRNAs that are critical to normal lens development and to RG function. These findings demonstrate a role for RGs in vertebrate organogenesis.
- Published
- 2011
- Full Text
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6. Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia.
- Author
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Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, Down J, Denaro M, Brady T, Westerman K, Cavallesco R, Gillet-Legrand B, Caccavelli L, Sgarra R, Maouche-Chrétien L, Bernaudin F, Girot R, Dorazio R, Mulder GJ, Polack A, Bank A, Soulier J, Larghero J, Kabbara N, Dalle B, Gourmel B, Socie G, Chrétien S, Cartier N, Aubourg P, Fischer A, Cornetta K, Galacteros F, Beuzard Y, Gluckman E, Bushman F, Hacein-Bey-Abina S, and Leboulch P
- Subjects
- Adolescent, Blood Cells cytology, Blood Cells metabolism, Bone Marrow Cells cytology, Bone Marrow Cells metabolism, Child, Preschool, Clone Cells metabolism, Gene Expression, Genetic Vectors genetics, HMGA2 Protein genetics, Homeostasis, Humans, Lentivirus genetics, Male, MicroRNAs genetics, Organ Specificity, RNA, Messenger analysis, RNA, Messenger genetics, Time Factors, Transcriptional Activation, Young Adult, beta-Thalassemia metabolism, Blood Transfusion, Genetic Therapy, HMGA2 Protein metabolism, beta-Globins genetics, beta-Globins metabolism, beta-Thalassemia genetics, beta-Thalassemia therapy
- Abstract
The β-haemoglobinopathies are the most prevalent inherited disorders worldwide. Gene therapy of β-thalassaemia is particularly challenging given the requirement for massive haemoglobin production in a lineage-specific manner and the lack of selective advantage for corrected haematopoietic stem cells. Compound β(E)/β(0)-thalassaemia is the most common form of severe thalassaemia in southeast Asian countries and their diasporas. The β(E)-globin allele bears a point mutation that causes alternative splicing. The abnormally spliced form is non-coding, whereas the correctly spliced messenger RNA expresses a mutated β(E)-globin with partial instability. When this is compounded with a non-functional β(0) allele, a profound decrease in β-globin synthesis results, and approximately half of β(E)/β(0)-thalassaemia patients are transfusion-dependent. The only available curative therapy is allogeneic haematopoietic stem cell transplantation, although most patients do not have a human-leukocyte-antigen-matched, geno-identical donor, and those who do still risk rejection or graft-versus-host disease. Here we show that, 33 months after lentiviral β-globin gene transfer, an adult patient with severe β(E)/β(0)-thalassaemia dependent on monthly transfusions since early childhood has become transfusion independent for the past 21 months. Blood haemoglobin is maintained between 9 and 10 g dl(-1), of which one-third contains vector-encoded β-globin. Most of the therapeutic benefit results from a dominant, myeloid-biased cell clone, in which the integrated vector causes transcriptional activation of HMGA2 in erythroid cells with further increased expression of a truncated HMGA2 mRNA insensitive to degradation by let-7 microRNAs. The clonal dominance that accompanies therapeutic efficacy may be coincidental and stochastic or result from a hitherto benign cell expansion caused by dysregulation of the HMGA2 gene in stem/progenitor cells.
- Published
- 2010
- Full Text
- View/download PDF
7. Apc inhibition of Wnt signaling regulates supernumerary tooth formation during embryogenesis and throughout adulthood.
- Author
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Wang XP, O'Connell DJ, Lund JJ, Saadi I, Kuraguchi M, Turbe-Doan A, Cavallesco R, Kim H, Park PJ, Harada H, Kucherlapati R, and Maas RL
- Subjects
- Adenomatous Polyposis Coli Protein genetics, Animals, Cells, Cultured, Embryonic Development, Fibroblast Growth Factor 8 genetics, Fibroblast Growth Factor 8 metabolism, MSX1 Transcription Factor genetics, MSX1 Transcription Factor metabolism, Mice, Mice, Transgenic, Signal Transduction, Tooth, Supernumerary metabolism, Wnt Proteins genetics, beta Catenin genetics, beta Catenin metabolism, Adenomatous Polyposis Coli Protein physiology, Tooth, Supernumerary embryology, Wnt Proteins metabolism
- Abstract
The ablation of Apc function or the constitutive activation of beta-catenin in embryonic mouse oral epithelium results in supernumerary tooth formation, but the underlying mechanisms and whether adult tissues retain this potential are unknown. Here we show that supernumerary teeth can form from multiple regions of the jaw and that they are properly mineralized, vascularized, innervated and can start to form roots. Even adult dental tissues can form new teeth in response to either epithelial Apc loss-of-function or beta-catenin activation, and the effect of Apc deficiency is mediated by beta-catenin. The formation of supernumerary teeth via Apc loss-of-function is non-cell-autonomous. A small number of Apc-deficient cells is sufficient to induce surrounding wild-type epithelial and mesenchymal cells to participate in the formation of new teeth. Strikingly, Msx1, which is necessary for endogenous tooth development, is dispensable for supernumerary tooth formation. In addition, we identify Fgf8, a known tooth initiation marker, as a direct target of Wnt/beta-catenin signaling. These studies identify key mechanistic features responsible for supernumerary tooth formation.
- Published
- 2009
- Full Text
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8. Modulatory subdomains of the HS2 enhancer differentially regulate enhancer activity in erythroid cells at different developmental stages.
- Author
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Cavallesco R and Tuan D
- Subjects
- Adult, Animals, Culture Techniques, Humans, Mice, Promoter Regions, Genetic, Restriction Mapping, Transfection, Tumor Cells, Cultured, Enhancer Elements, Genetic, Erythroid Precursor Cells metabolism, Globins genetics
- Abstract
The HS2 enhancer in the locus control region of human beta-like globin genes displays developmental-stage-independent enhancer function. The mechanism by which it regulates the transcription of the globin genes in erythroid cells throughout development is not fully understood. In this paper we dissect the HS2 enhancer into an enhancer core and five modulatory subdomains M1 to M5. The enhancer core possesses developmental-stage-independent enhancer activity. The modulatory subdomains by themselves do not possess such enhancer activity, but they apparently respond to environmental signals and modulate enhancer core activity in a developmental-stage specific manner. M1 located 5' of the core strongly stimulates core activity in K562 cells at the embryonic stage. M2 and M3 located 3' of the core strongly stimulate core activity in MEL cells at the adult stage. Moreover, M3 suppresses core activity at the embryonic stage and exhibits an adult-stage-selector activity. These findings indicate that the apparent developmental-stage-independence of the HS2 enhancer is a result of multiple interactions between the core and the modulatory subdomains located both near and far from the core.
- Published
- 1997
- Full Text
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9. Characterization of a human globin enhancer element.
- Author
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Tuan DY, Solomon WB, Cavallesco R, Huang G, and London IM
- Subjects
- Animals, Embryonic and Fetal Development, Erythroid Precursor Cells metabolism, Genes, Globins biosynthesis, Humans, Mice, Organ Specificity, Recombinant Fusion Proteins biosynthesis, Transcription, Genetic, Tumor Cells, Cultured, Enhancer Elements, Genetic, Gene Expression Regulation, Globins genetics
- Published
- 1989
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