Angiotensin-converting enzyme homolog Ance is regulated by Mad and Pannier and affects Dpp signaling

Abstract

Angiotensin-converting enzyme (ACE) is an evolutionarily conserved peptidyl dipeptidase. Mammalian ACE converts angiotensin I to the active vasoconstrictor angiotensin II, thus playing a critical role for homeostasis of the renin-angiotensin system. In Drosophila, a conserved ACE homolog Ance is expressed in specific regions of developing tissues, but its function has not been clearly identified. Here we provide evidence that Ance expression is regulated by a combination of two transcription factors and plays a role in the modulation of Dpp signaling in developing imaginal discs. We demonstrate that Ance expression in eye and wing discs depends on Dpp signaling. The Mad binding site of the Ance regulatory region is essential for Ance expression, implying a direct regulation by Mad. Ance expression in imaginal discs is also regulated by the GATA family transcription factor Pannier (Pnr). Pnr directly regulates Ance expression by binding to a GATA site of the Ance enhancer. In addition, Pnr and Mad physically and genetically interact. Ance null mutants show no visible phenotypes. However, a reduction of Ance causes developmental defects when Dpp signaling is partially compromised. Furthermore, we show that ACE expression in HEK293 human kidney cells is impaired by depletion of either SMAD2 or GATA4. Taken together, this study reveals a new function of Ance in the modulation of Dpp signaling and a cooperative mechanism of Ance regulation by Mad and Pnr. My data also suggest a conserved transcriptional regulation of mammalian ACE.