GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis.
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.
Lepore
John J
JJ
Molecular Cardiology Research Center and the Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Mericko
Patricia A
PA
Cheng
Lan
L
Lu
Min Min
MM
Morrisey
Edward E
EE
Parmacek
Michael S
MS
D000818:Animals; D001011:Aorta / Q000254:growth & development / Q000378:metabolism; D018376:Cardiovascular Abnormalities / Q000235:genetics*; D002454:Cell Differentiation; D005260:Female; D050993:GATA6 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D018390:Gene Targeting; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000235:genetics; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D009024:Morphogenesis; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D032389:Myocytes, Smooth Muscle; D009432:Neural Crest / Q000378:metabolism*; D039961:Semaphorins / Q000235:genetics* / Q000378:metabolism; D013045:Species Specificity; D014162:Transfection
D050993:GATA6 Transcription Factor; D039961:Semaphorins; C510203:semaphorin 3C protein, mouse