TY - JOUR
T1 - Direct activation of a GATA6 cardiac enhancer by Nkx2.5
T2 - Evidence for a reinforcing regulatory network of Nkx2.5 and GATA transcription factors in the developing heart
AU - Molkentin, Jeffery D.
AU - Antos, Christopher
AU - Mercer, Brian
AU - Taigen, Tyler
AU - Miano, Joseph M.
AU - Olson, Eric N.
N1 - Funding Information:
We thank A. Wu for technical assistance in generating transgenic mice and K. Yutzey for insightful discussions. This work was supported by grants from the NIH, The Muscular Dystrophy Association, and the American Heart Association to E.N.O. J.D.M. was supported by a postdoctoral fellowship from the NIH, an American Heart Association Scientist Development Grant, and NIH R01HL60562.
PY - 2000/1/15
Y1 - 2000/1/15
N2 - The zinc finger transcription factors GATA4, -5, and -6 and the homeodomain protein Nkx2.5 are expressed in the developing heart and have been shown to activate a variety of cardiac-specific genes. To begin to define the regulatory relationships between these cardiac transcription factors and to understand the mechanisms that control their expression during cardiogenesis, we analyzed the mouse GATA6 gene for regulatory elements sufficient to direct cardiac expression during embryogenesis. Using β- galactosidase fusion constructs in transgenic mice, a 4.3-kb 5' regulatory region that directed transcription specifically in the cardiac lineage, beginning at the cardiac crescent stage, was identified. Thereafter, transgene expression became compartmentalized to the outflow tract, a portion of the right ventricle, and a limited region of the common atrial chamber of the embryonic heart. Further dissection of this regulatory region identified a 1.8-kb cardiac-specific enhancer that recapitulated the expression pattern of the larger region when fused to a heterologous promoter and a smaller 500- bp subregion that retained cardiac expression, but was quantitatively weaker. The GATA6 cardiac enhancer contained a binding site for Nkx2.5 that was essential for cardiac-specific expression in transgenic mice. These studies demonstrate that GATA6 is a direct target gene for Nkx2.5 in the developing heart and reveal a mutually reinforcing regulatory network of Nkx2.5 and GATA transcription factors during cardiogenesis.
AB - The zinc finger transcription factors GATA4, -5, and -6 and the homeodomain protein Nkx2.5 are expressed in the developing heart and have been shown to activate a variety of cardiac-specific genes. To begin to define the regulatory relationships between these cardiac transcription factors and to understand the mechanisms that control their expression during cardiogenesis, we analyzed the mouse GATA6 gene for regulatory elements sufficient to direct cardiac expression during embryogenesis. Using β- galactosidase fusion constructs in transgenic mice, a 4.3-kb 5' regulatory region that directed transcription specifically in the cardiac lineage, beginning at the cardiac crescent stage, was identified. Thereafter, transgene expression became compartmentalized to the outflow tract, a portion of the right ventricle, and a limited region of the common atrial chamber of the embryonic heart. Further dissection of this regulatory region identified a 1.8-kb cardiac-specific enhancer that recapitulated the expression pattern of the larger region when fused to a heterologous promoter and a smaller 500- bp subregion that retained cardiac expression, but was quantitatively weaker. The GATA6 cardiac enhancer contained a binding site for Nkx2.5 that was essential for cardiac-specific expression in transgenic mice. These studies demonstrate that GATA6 is a direct target gene for Nkx2.5 in the developing heart and reveal a mutually reinforcing regulatory network of Nkx2.5 and GATA transcription factors during cardiogenesis.
KW - Cardiac
KW - GATA6
KW - Nkx2.5
UR - http://www.scopus.com/inward/record.url?scp=0034650312&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034650312&partnerID=8YFLogxK
U2 - 10.1006/dbio.1999.9544
DO - 10.1006/dbio.1999.9544
M3 - Article
C2 - 10625555
AN - SCOPUS:0034650312
SN - 0012-1606
VL - 217
SP - 301
EP - 309
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -