An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation

被引：52

作者：

Nadeau, Mathieu ^{[1
,2
]}

Georges, Romain O. ^{[1
,2
]}

Laforest, Brigitte ^{[1
,2
]}

Yamak, Abir ^{[1
,3
]}

Lefebvre, Chantal ^{[1
,2
]}

Beauregard, Janie ^{[1
,3
]}

Paradis, Pierre ^{[1
]}

Bruneau, Benoit G. ^{[4
]}

Andelfinger, Gregor ^{[1
,5
]}

Nemer, Mona ^{[1
,3
]}

机构：

[1] Univ Montreal, Res Unit Cardiac Growth & Differentiat, Montreal, PQ H3C 3J7, Canada

[2] Univ Montreal, Program Mol Biol, Montreal, PQ H3C 3J7, Canada

[3] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON K1N 6N5, Canada

[4] Univ Calif San Francisco, Dept Pediat, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA

[5] Hop Ste Justine, Dept Cardiovasc Genet, Montreal, PQ H3T 1C5, Canada

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2010年 / 107卷 / 45期

关键词：

heart development; Holt-Oram syndrome; CONGENITAL HEART-DISEASE; NITRIC-OXIDE SYNTHASE; HOLT-ORAM-SYNDROME; CUSHION CELL-PROLIFERATION; GENE-EXPRESSION; TRANSCRIPTION FACTOR; CARDIOVASCULAR-DISEASE; SCIENTIFIC STATEMENT; CURRENT KNOWLEDGE; CARDIAC VALVES;

D O I：

10.1073/pnas.0914888107

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：19356 / 19361

页数：6