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

J Clin Invest. 2006 Apr;116(4):929-39. doi: 10.1172/JCI27363. Epub 2006 Mar 23.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / growth & development
  • Aorta / metabolism
  • Cardiovascular Abnormalities / genetics*
  • Cell Differentiation
  • Female
  • GATA6 Transcription Factor / genetics
  • GATA6 Transcription Factor / metabolism*
  • Gene Deletion
  • Gene Targeting
  • Heart / embryology*
  • Heart Defects, Congenital / genetics
  • In Situ Hybridization
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Genetic
  • Morphogenesis
  • Muscle, Smooth, Vascular / metabolism
  • Myocytes, Smooth Muscle
  • Neural Crest / metabolism*
  • Semaphorins / genetics*
  • Semaphorins / metabolism
  • Species Specificity
  • Transfection

Substances

  • GATA6 Transcription Factor
  • Semaphorins
  • semaphorin 3C protein, mouse