T-box genes and retinoic acid signaling regulate the segregation of arterial and venous pole progenitor cells in the murine second heart field
| Autor: | Estelle Jullian, Charlotte Thellier, Magali Théveniau-Ruissy, Stéphane Zaffran, Nicolas Bertrand, Robert G. Kelly, Rachel Sturny, Christopher De Bono, Claudio Cortes, Sonia Stefanovic |
|---|---|
| Přispěvatelé: | Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Heart Defects
Congenital 0301 basic medicine TBX1 Mesoderm [SDV]Life Sciences [q-bio] Population Retinoic acid Mice Transgenic Tretinoin Biology Heart Septal Defects Atrial Mice 03 medical and health sciences chemistry.chemical_compound DiGeorge Syndrome Genetics medicine Animals Abnormalities Multiple Upper Extremity Deformities Congenital Progenitor cell education Molecular Biology Genetics (clinical) Progenitor Regulation of gene expression education.field_of_study Heart Septal Defects Stem Cells Gene Expression Regulation Developmental General Medicine Coronary Vessels Cell biology 030104 developmental biology medicine.anatomical_structure T-box chemistry T-Box Domain Proteins Lower Extremity Deformities Congenital Signal Transduction |
| Zdroj: | Human Molecular Genetics Human Molecular Genetics, Oxford University Press (OUP), 2018, 27 (21), pp.3747-3760. ⟨10.1093/hmg/ddy266⟩ Human Molecular Genetics, 2018, 27 (21), pp.3747-3760. ⟨10.1093/hmg/ddy266⟩ |
| ISSN: | 0964-6906 1460-2083 |
| DOI: | 10.1093/hmg/ddy266⟩ |
| Popis: | International audience; The arterial and venous poles of the mammalian heart are hotspots of congenital heart defects (CHD) such as those observed in 22q11.2 deletion (or DiGeorge) and Holt-Oram syndromes. These regions of the heart are derived from late differentiating cardiac progenitor cells of the Second Heart Field (SHF) located in pharyngeal mesoderm contiguous with the elongating heart tube. The T-box transcription factor Tbx1, encoded by the major 22q11.2 deletion syndrome gene, regulates SHF addition to both cardiac poles from a common progenitor population. Despite the significance of this cellular addition the mechanisms regulating the deployment of common progenitor cells to alternate cardiac poles remain poorly understood. Here we demonstrate that Tbx5, mutated in Holt-Oram syndrome and essential for venous pole development, is activated in Tbx1 expressing cells in the posterior region of the SHF at early stages of heart tube elongation. A subset of the SHF transcriptional program, including Tbx1 expression, is subsequently downregulated in Tbx5 expressing cells, generating a transcriptional boundary between Tbx1-positive arterial pole and Tbx5-positive venous pole progenitor cell populations. We show that normal downregulation of the definitive arterial pole progenitor cell program in the posterior SHF is dependent on both Tbx1 and Tbx5. Furthermore, retinoic acid (RA) signaling is required for Tbx5 activation in Tbx1-positive cells and blocking RA signaling at the time of Tbx5 activation results in atrioventricular septal defects at fetal stages. Our results reveal sequential steps of cardiac progenitor cell patterning and provide mechanistic insights into the origin of common forms of CHD. |
| Databáze: | OpenAIRE |
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