Activation of Tolloid-like 1 gene expression by the cardiac  specific homeobox gene Nkx2-5.
Mammalian Tolloid-like 1 (Tll-1) is a pleiotropic metalloprotease that is expressed by a small subset of cells within the precardiac mesoderm and is necessary for proper heart development. Following heart tube formation Tll-1 is expressed by the endocardium and regions of myocardium overlying the region of the muscular interventricular septum. Mutations in Tll-1 lead to embryonic lethality due to cardiac defects. We demonstrate that the Tll-1promoter contains Nkx2-5 binding sites and that the Tll-1 promoter is activated by and directly binds Nkx2-5.Tll-1 expression is ablated by a dominant negative Nkx2-5 or by mutation of the Nkx2-5 binding sites within theTll-1 promoter. In vivo, Tll-1 expression is decreased in the hearts of Nkx2-5 knockout embryos when compared with hemizygous and wild-type embryos. These results show that Nkx2-5 is a direct activator of Tll-1 expression and provide insight into the mechanism of the defects found in both the Tll-1 and Nkx2-5 knockout mice.
University of South Dakota Sanford School of Medicine, Division of Basic Biomedical Sciences, 414 E. Clark St., Vermillion, SD 57069, USA.
Inna
I
Sabirzhanova
Boris
B
Sabirzhanov
Joy
J
Bjordahl
Jessica
J
Brandt
Patrick Y
PY
Jay
Timothy G
TG
Clark
D000818:Animals; D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009206:Myocardium / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D011784:Quail; D055394:Tolloid-Like Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D014157:Transcription Factors; D055394:Tolloid-Like Metalloproteinases