Tbx1 coordinates addition of posterior second heart field progenitor cells to the arterial and venous poles of the heart.

Cardiac progenitor cells from the second heart field (SHF) contribute to rapid growth of the embryonic heart, giving rise to right ventricular and outflow tract (OFT) myocardium at the arterial pole of the heart, and atrial myocardium at the venous pole. Recent clonal analysis and cell-tracing experiments indicate that a common progenitor pool in the posterior region of the SHF gives rise to both OFT and atrial myocytes. The mechanisms regulating deployment of this progenitor pool remain unknown.
To evaluate the role of TBX1, the major gene implicated in congenital heart defects in 22q11.2 deletion syndrome patients, in posterior SHF development.
Using transcriptome analysis, genetic tracing, and fluorescent dye-labeling experiments, we show that Tbx1-dependent OFT myocardium originates in Hox-expressing cells in the posterior SHF. In Tbx1 null embryos, OFT progenitor cells fail to segregate from this progenitor cell pool, leading to failure to expand the dorsal pericardial wall and altered positioning of the cardiac poles. Unexpectedly, addition of SHF cells to the venous pole of the heart is also impaired, resulting in abnormal development of the dorsal mesenchymal protrusion, and partially penetrant atrioventricular septal defects, including ostium primum defects.
Tbx1 is required for inflow as well as OFT morphogenesis by regulating the segregation and deployment of progenitor cells in the posterior SHF. Our results provide new insights into the pathogenesis of congenital heart defects and 22q11.2 deletion syndrome phenotypes.
AuthorsM Sameer Rana, Magali Théveniau-Ruissy, Christopher De Bono, Karim Mesbah, Alexandre Francou, Mayyasa Rammah, Jorge N Domínguez, Marine Roux, Brigitte Laforest, Robert H Anderson, Timothy Mohun, Stephane Zaffran, Vincent M Christoffels, Robert G Kelly
JournalCirculation research (Circ Res) Vol. 115 Issue 9 Pg. 790-9 (Oct 10 2014) ISSN: 1524-4571 [Electronic] United States
PMID25190705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2014 American Heart Association, Inc.
Chemical References
  • T-Box Domain Proteins
  • Tbx1 protein, mouse
  • Animals
  • Cell Lineage
  • Cell Movement
  • Cell Proliferation
  • Coronary Vessels (embryology, metabolism, pathology)
  • DiGeorge Syndrome (genetics, metabolism, pathology)
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental
  • Genetic Predisposition to Disease
  • Gestational Age
  • Heart (embryology)
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Morphogenesis
  • Myocardium (metabolism, pathology)
  • Phenotype
  • Signal Transduction
  • Stem Cells (metabolism, pathology)
  • T-Box Domain Proteins (deficiency, genetics, metabolism)

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