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 4

Effect of GATA-6 deletion on neural crest–derived SMC differentiation.

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Effect of GATA-6 deletion on neural crest–derived SMC differentiation. (...
(A–J) H&E staining (C, D, G, and H) and SMα-actin (SMA) immunohistochemistry (A, B, E, F, I, and J) of SM22Cre–GATA-6F/F (SMCre–) and SM22Cre+GATA-6F/F (SMCre+) embryos. Original magnification, ×100 (A–F); ×200 (G–J). (A and B) Frontal section through the pharyngeal arches in an E11.5 SMCre+ embryo (B) demonstrates normal formation of pharyngeal arches 3, 4, and 6 and SMA immunostaining in SMCs of the pharyngeal arch arteries and carotid arteries (car) similar to that in a normal SM22Cre– embryo (A). (C–F) In a representative E12.5 SMCre+ embryo (D and F), despite the presence of aortopulmonary window (APW), the structure of the vessel wall and the presence of SMA immunostaining in neural crest–derived SMCs in the vascular wall of the aorta and PA are not different compared with a normal SMCre– embryo (C and E). (G–J) Cross sections through the vascular walls of Ao and PA of an E18.5 SM22Cre– embryo (G and I) and the vascular wall of the truncus arteriosus (TA) of a SM22Cre+ embryo (H and J) demonstrate similar structure of the vessel wall and presence of SMA immunostaining neural crest–derived SMCs. (K) Quantitative RT-PCR of primary GATA-6F/F aortic SMCs infected with Ad-empty (Ctrl) or Ad-Cre (Cre) demonstrates that GATA-6 deletion does not change expression of mRNA encoding SMC-restricted cytoskeletal and contractile proteins. The ethidium-stained products amplified at the cycle threshold for each message and for control GAPDH are shown with the fold change in expression.