Jam2 Signaling Functions Downstream of Hand2 To Initiate The Formation Of Organ-Specific Vascular Progenitors In Zebrafish

The mechanisms regulating the formation of organ-specific vasculature are still poorly understood. We have previously identified a population of late-forming endothelial progenitor cells in zebrafish embryos (termed secondary vascular field, SVF), which emerge from the lateral plate mesoderm after 24 hpf stage, after blood circulation has been initiated. Here we investigate the functional role of SVF cells and the molecular mechanisms that govern the emergence of these SVF cells and their contribution to vasculature. We identified that the bHLH transcription factor Hand2 and Junctional Adhesion Molecule Jam2b are expressed in the SVF-forming region and are required for the emergence of SVF cells in zebrafish embryos. Time-lapse imaging and jam2b:Cre based lineage tracing showed that SVF cells serve as the major source of the intestinal vasculature, including the supraintestinal artery (SIA) and subintestinal vein (SIV), which are subsequently remodeled to provide the blood flow to many internal organs. To analyze the functional role of jam2b and a related jam2a gene in vascular development, we generated double maternal-zygotic jam2a; jam2b mutants, which display a greatly reduced number of SVF cells and show defects in the intestinal vasculature development. Further analysis showed that hand2 functions in the SVF-forming region upstream of jam2b and is required to induce expression of transcription factor etv2/etsrp, a known master regulator of vasculogenesis. In summary, our results identify new roles for Jam2 signaling and Hand2 function in the emergence of organ-specific vascular progenitors. The presence of similar progenitors in mammalian embryos suggests that this mechanism is evolutionarily conserved.