An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation.
In humans, septal defects are among the most prevalent congenital heart diseases, but their cellular and molecular origins are not fully understood. We report that transcription factor Tbx5 is present in a subpopulation of endocardial cells and that its deletion therein results in fully penetrant, dose-dependent atrial septal defects in mice. Increased apoptosis of endocardial cells lacking Tbx5, as well as neighboring TBX5-positive myocardial cells of the atrial septum through activation of endocardial NOS (Nos3), is the underlying mechanism of disease. Compound Tbx5 and Nos3 haploinsufficiency in mice worsens the cardiac phenotype. The data identify a pathway for endocardial cell survival and unravel a cell-autonomous role for Tbx5 therein. The finding that Nos3, a gene regulated by many congenital heart disease risk factors including stress and diabetes, interacts genetically with Tbx5 provides a molecular framework to understand gene-environment interaction in the setting of human birth defects.
Research Unit in Cardiac Growth and Differentiation and Molecular Biology Program, Université de Montréal, Montréal, QC, Canada H3C 3J7.
Mathieu
M
Nadeau
Romain O
RO
Georges
Brigitte
B
Laforest
Abir
A
Yamak
Chantal
C
Lefebvre
Janie
J
Beauregard
Pierre
P
Paradis
Benoit G
BG
Bruneau
Gregor
G
Andelfinger
Mona
M
Nemer
D000818:Animals; D054087:Atrial Septum / Q000166:cytology* / Q000473:pathology; D002470:Cell Survival; D004699:Endocardium / Q000166:cytology* / Q000473:pathology; D050991:GATA4 Transcription Factor / Q000502:physiology*; D057895:Haploinsufficiency; D006330:Heart Defects, Congenital / Q000209:etiology / Q000235:genetics; D006331:Heart Diseases / Q000151:congenital*; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000502:physiology*; D010641:Phenotype; D020825:T-Box Domain Proteins / Q000032:analysis / Q000502:physiology*
D050991:GATA4 Transcription Factor; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse