Activation of Tolloid-like 1 gene expression by the cardiac specific homeobox gene Nkx2-5

Inna Sabirzhanova, Boris Sabirzhanov, Joy Bjordahl, Jessica Brandt, Patrick Y. Jay, Timothy G. Clark

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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-1 promoter 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 the Tll-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.

Original languageEnglish
Pages (from-to)403-410
Number of pages8
JournalDevelopment Growth and Differentiation
Issue number4
StatePublished - May 2009


  • Endocardium
  • Nkx2-5
  • Precardiac mesoderm
  • Tolloid-like 1


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