GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis
John J. Lepore, … , Edward E. Morrisey, Michael S. Parmacek
John J. Lepore, … , Edward E. Morrisey, Michael S. Parmacek
Published April 3, 2006
Citation Information: J Clin Invest. 2006;116(4):929-939. https://doi.org/10.1172/JCI27363.
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Research Article Cardiology

GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis

Abstract

GATA transcription factors play critical roles in restricting cell lineage differentiation during development. Here, we show that conditional inactivation of GATA-6 in VSMCs results in perinatal mortality from a spectrum of cardiovascular defects, including interrupted aortic arch and persistent truncus arteriosus. Inactivation of GATA-6 in neural crest recapitulates these abnormalities, demonstrating a cell-autonomous requirement for GATA-6 in neural crest–derived SMCs. Surprisingly, the observed defects do not result from impaired SMC differentiation but rather are associated with severely attenuated expression of semaphorin 3C, a signaling molecule critical for both neuronal and vascular patterning. Thus, the primary function of GATA-6 during cardiovascular development is to regulate morphogenetic patterning of the cardiac outflow tract and aortic arch. These findings provide new insights into the conserved functions of the GATA-4, -5, and -6 subfamily members and identify GATA-6 and GATA-6–regulated genes as candidates involved in the pathogenesis of congenital heart disease.

Authors

John J. Lepore, Patricia A. Mericko, Lan Cheng, Min Min Lu, Edward E. Morrisey, Michael S. Parmacek

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Figure 2

Cardiovascular abnormalities produced by conditional GATA-6 deletion.

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Cardiovascular abnormalities produced by conditional GATA-6 deletion. Ao...
Aortic arch patterning and cardiac outflow tract septation were examined in E18.5 GATA-6F/F(Cre–; A and F–I), SMCre+GATA-6F/F (SMCre+; B, C, and K–N), and Wnt1Cre+GATA-6 (WCre+; D, E, J, and O) embryos using polymer vascular casting (A–E) and H&E staining (F–O). (A) In normal aortic arch patterning, the ascending aorta (AAo) and pulmonary artery (PA) are distinct, septated vessels. The ductus arteriosus (DA) is patent and connects the PA to the proximal descending aorta (DAo). The right subclavian artery (RS) branches from the AAo. (B) SMCre+ embryo demonstrating truncus arteriosus (TA) and hypoplastic aortic arch (arch). (C) SMCre+ embryo demonstrating interrupted aortic arch (IAA). (D) WCre+ embryo demonstrating TA, hypoplastic arch, and retroesophageal right subclavian artery (RERS). (E) WCre+ embryo demonstrating IAA. (F–I) Serial histological sections through the heart and great vessels of a normal embryo. (F) The DA connects the PA to the DAo. The RS branches from the AAo. (G and H) The AAo and PA are distinct, septated vessels. The pulmonary valve (PV) is shown. (I) An intact ventricular septum (arrow) separates the right and left ventricles. (K–N) Corresponding serial sections from a SMCre+ embryo. (K) A RERS branches from the DAo and travels posterior to the esophagus (E). (L–N) There is single outflow tract vessel, or TA; a single, common aorticopulmonary valve (APV); and a membranous ventricular septal defect (VSD). (J and O) Representative WntCre+ embryo exhibiting TA and VSD. Original magnification, ×20 (A–E); ×40 (F–O).