Abstract
During early heart morphogenesis cardiac cells migrate in two bilateral opposing rows, meet at the dorsal midline and fuse to form a hollow tube known as the primary heart field in vertebrates or dorsal vessel (DV) in Drosophila. Guidance receptors are thought to mediate this evolutionarily conserved process. A core of transcription factors from the NK2, GATA and T-box families are also believed to orchestrate this process in both vertebrates and invertebrates. Nevertheless, whether they accomplish their function, at least in part, through direct or indirect transcriptional regulation of guidance receptors is currently unknown. In our work, we demonstrate how Tinman (Tin), the Drosophila homolog of the Nkx-2.5 transcription factor, regulates the Unc-5 receptor during DV tube morphogenesis. We use genetics, expression analysis with single cell mRNA resolution and enhancer-reporter assays in vitro or in vivo to demonstrate that Tin is required for Unc-5 receptor expression specifically in cardioblasts. We show that Tin can bind to evolutionary conserved sites within an Unc-5 DV enhancer and that these sites are required for Tin-dependent transactivation both in vitro and in vivo.
Highlights
Stages of heart development, both in vertebrates and invertebrates, include the migration of bilaterally paired condensations of cardiac precursors and the formation of a linear tube
Cardiac mesoderm specification is strongly dependent on the combined actions of several transcription factors including the Doc family of T-box transcription factors and tin [2, 23, 24]
Mesodermal expression of Unc-5 is dependent on the combined actions of tin and Doc [23] and Unc-5 cardiogenic mesoderm enhancers are bound by tin, Doc and Pnr [24]
Summary
Stages of heart development, both in vertebrates and invertebrates, include the migration of bilaterally paired condensations of cardiac precursors and the formation of a linear tube. The tube is formed once these symmetrical groups of mesodermal cells meet, and attach to each other leaving a luminal space between them [1, 2]. The coordinated migration of these mesodermal cells, bilateral interaction and the preservation of a lumen require complex interactions of multiple guidance receptors in Drosophila during DV morphogenesis [3,4,5,6,7,8]. Vertebrate homologs of the same ligand/receptor systems are expressed in the developing heart in PLOS ONE | DOI:10.1371/journal.pone.0137688. Vertebrate homologs of the same ligand/receptor systems are expressed in the developing heart in PLOS ONE | DOI:10.1371/journal.pone.0137688 September 10, 2015
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