TY - JOUR
T1 - Cardiac-specific activity of an Nkx2-5 enhancer requires an evolutionarily conserved Smad binding site
AU - Lien, Ching Ling
AU - McAnally, John
AU - Richardson, James A.
AU - Olson, Eric N.
N1 - Funding Information:
We thank Drs. J. Massagué and A. Hata for Smad plasmids, A. Lassar and K.-H. Lee for providing DNA sequence information, and K. Yutzey for sharing results prior to publication. We are grateful to Dr. M. Chao and A. Tizenor for assistance with graphics and members of the Olson laboratory for input and support. E.N.O. was supported by grants from the National Institutes of Health, the D. W. Reynolds Cardiovascular Clinical Research Center, the Robert A. Welch Foundation, and the W. G. McGowan Charitable Fund.
PY - 2002/4/15
Y1 - 2002/4/15
N2 - Heart formation in vertebrates and fruit flies requires signaling by bone morphogenetic proteins (BMPs) to cardiogenic mesodermal precursor cells. The vertebrate homeobox gene Nkx2-5 and its Drosophila ortholog, tinman, are the earliest known markers for the cardiac lineage. Transcriptional activation of tinman expression in the cardiac lineage is dependent on a mesoderm-specific enhancer that binds Smad proteins, which activate transcription in response to BMP signaling, and Tinman, which maintains its own expression through an autoregulatory loop. Here, we show that an evolutionarily conserved, cardiac-specific enhancer of the mouse Nkx2-5 gene contains multiple Smad binding sites, as well as a binding site for Nkx2-5. A single Smad site is required for enhancer activity at early and late stages of heart development in vivo, whereas the Nkx2-5 site is not required for enhancer activity. These findings demonstrate that Nkx2-5, like tinman, is a direct target for transcriptional activation by Smad proteins; however, the independence of this Nkx2-5 enhancer of Nkx2-5 binding suggests a fundamental difference in the transcriptional circuitry for activation of Nkx2-5 and tinman expression during cardiogenesis in vertebrates and fruit flies.
AB - Heart formation in vertebrates and fruit flies requires signaling by bone morphogenetic proteins (BMPs) to cardiogenic mesodermal precursor cells. The vertebrate homeobox gene Nkx2-5 and its Drosophila ortholog, tinman, are the earliest known markers for the cardiac lineage. Transcriptional activation of tinman expression in the cardiac lineage is dependent on a mesoderm-specific enhancer that binds Smad proteins, which activate transcription in response to BMP signaling, and Tinman, which maintains its own expression through an autoregulatory loop. Here, we show that an evolutionarily conserved, cardiac-specific enhancer of the mouse Nkx2-5 gene contains multiple Smad binding sites, as well as a binding site for Nkx2-5. A single Smad site is required for enhancer activity at early and late stages of heart development in vivo, whereas the Nkx2-5 site is not required for enhancer activity. These findings demonstrate that Nkx2-5, like tinman, is a direct target for transcriptional activation by Smad proteins; however, the independence of this Nkx2-5 enhancer of Nkx2-5 binding suggests a fundamental difference in the transcriptional circuitry for activation of Nkx2-5 and tinman expression during cardiogenesis in vertebrates and fruit flies.
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U2 - 10.1006/dbio.2002.0603
DO - 10.1006/dbio.2002.0603
M3 - Article
C2 - 11944935
AN - SCOPUS:0037090906
SN - 0012-1606
VL - 244
SP - 257
EP - 266
JO - Developmental Biology
JF - Developmental Biology
IS - 2
ER -