Control of early cardiac-specific transcription of Nkx2-5 by a GATA-dependent enhancer

Ching Ling Lien, Chuanzhen Wu, Brian Mercer, Robert Webb, James A. Richardson, Eric N. Olson

Research output: Contribution to journalArticle

212 Citations (Scopus)

Abstract

The homeobox gene Nkx2-5 is the earliest known marker of the cardiac lineage in vertebrate embryos. Nkx2-5 expression is first detected in mesodermal cells specified to form heart at embryonic day 7.5 in the mouse and expression is maintained throughout the developing and adult heart. In addition to the heart, Nkx2-5 is transiently expressed in the developing pharynx, thyroid and stomach. To investigate the mechanisms that initiate cardiac transcription during embryogenesis, we analyzed the Nkx2-5 upstream region for regulatory elements sufficient to direct expression of a lacZ transgene in the developing heart of transgenic mice. We describe a cardiac enhancer, located about 9 kilobases upstream of the Nkx2-5 gene, that fully recapitulates the expression pattern of the endogenous gene in cardiogenic precursor cells from the onset of cardiac lineage specification and throughout the linear and looping heart tube. Thereafter, as the atrial and ventricular chambers become demarcated, enhancer activity becomes restricted to the developing right ventricle. Transcription of Nkx2-5 in pharynx, thyroid and stomach is controlled by regulatory elements separable from the cardiac enhancer. This distal cardiac enhancer contains a high-affinity binding site for the cardiac-restricted zinc finger transcription factor GATA4 that is essential for transcriptional activity. These results reveal a novel GATA-dependent mechanism for activation of Nkx2-5 transcription in the developing heart and indicate that regulation of Nkx2-5 is controlled in a modular manner, with multiple regulatory regions responding to distinct transcriptional networks in different compartments of the developing heart.

Original languageEnglish (US)
Pages (from-to)75-84
Number of pages10
JournalDevelopment
Volume126
Issue number1
StatePublished - Jan 1999

Fingerprint

Nucleic Acid Regulatory Sequences
Pharynx
Stomach
GATA4 Transcription Factor
Thyroid Gland
Homeobox Genes
Gene Regulatory Networks
Zinc Fingers
Transgenes
Transgenic Mice
Genes
Heart Ventricles
Embryonic Development
Vertebrates
Embryonic Structures
Binding Sites

Keywords

  • Cardiac lineage
  • GATA
  • Mesoderm
  • Nkx2-5
  • Transcription

ASJC Scopus subject areas

  • Anatomy
  • Cell Biology

Cite this

Control of early cardiac-specific transcription of Nkx2-5 by a GATA-dependent enhancer. / Lien, Ching Ling; Wu, Chuanzhen; Mercer, Brian; Webb, Robert; Richardson, James A.; Olson, Eric N.

In: Development, Vol. 126, No. 1, 01.1999, p. 75-84.

Research output: Contribution to journalArticle

Lien, Ching Ling ; Wu, Chuanzhen ; Mercer, Brian ; Webb, Robert ; Richardson, James A. ; Olson, Eric N. / Control of early cardiac-specific transcription of Nkx2-5 by a GATA-dependent enhancer. In: Development. 1999 ; Vol. 126, No. 1. pp. 75-84.
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