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Tbx1 Coordinates Addition of Posterior Second Heart Field Progenitor Cells to the Arterial and Venous Poles of the Heart

Lookup NU author(s): Professor Bob Anderson


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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 (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.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 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.Conclusions: 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.

Publication metadata

Author(s): Rana MS, Theveniau-Ruissy M, De Bono C, Mesbah K, Francou A, Rammah M, Dominguez JN, Roux M, Laforest B, Anderson RH, Mohun T, Zaffran S, Christoffels VM, Kelly RG

Publication type: Article

Publication status: Published

Journal: Circulation Research

Year: 2014

Volume: 115

Issue: 9

Pages: 790-799

Print publication date: 10/10/2014

Online publication date: 04/09/2014

Acceptance date: 04/09/2014

ISSN (print): 0009-7330

ISSN (electronic): 1524-4571

Publisher: Lippincott Williams & Wilkins


DOI: 10.1161/CIRCRESAHA.115.305020


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Funder referenceFunder name
017.004.040Netherlands Organization for Scientific Research
864.05.006Netherlands Organization for Scientific Research
ANR-13-BSV2-0003-02Agence Nationale pour la Recherche (Transcardiac project)
Equipe FRM DEQ20110421300Fondation pour la Recherche Medicale
HEALTH-2007-B-2234634European Commission under the FP7 Integrated Project CardioGeNet
ITN-2011-GA289600Marie Curie Initial Training Network CardioNet
U117562103Medical Research Council