Tbx1 Coordinates Addition of Posterior Second Heart Field Progenitor Cells to the Arterial and Venous Poles of the Heart
Rationale: 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 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 outflow tract and atrial myocytes. The mechanisms regulating deployment of this progenitor pool remain unknown.
Objective: To evaluate the role of TBX1, the major gene implicated in congenital heart defects in 22q11.2 deletion syndrome patients, in posterior SHF development.
Methods and Results: Using transcriptome analysis, genetic tracing, and DiI labeling experiments, we show that Tbx1-dependent outflow tract myocardium originates in Hox-expressing cells in the posterior SHF. In Tbx1 null embryos, outflow tract 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.
Conclusions: Tbx1 is required for inflow as well as outflow tract morphogenesis by regulating the segregation and deployment of progenitor cells in the posterior SHF. Our results provide new insights into the etiology of congenital heart defects and 22q11.2 deletion syndrome phenotypes.
- Second heart field
- 22q11.2 deletion syndrome
- heart development
- heart defects, congenital
- cardiac progenitor cells
- cardiac embryology
- Received August 8, 2014.
- Revision received August 27, 2014.
- Accepted September 4, 2014.