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 withinthe precardiac mesoderm and is necessary for proper heart development. Following heart tube formation Tll-1 isexpressed by the endocardium and regions of myocardium overlying the region of the muscular interventricularseptum. 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.