The report is published in the June 1st issue of Genes & Development.
During embryogenesis, a population of cells, called endothelial cells, give rise to the vascular and lymphatic system. Extensive research into the genetic basis of vascular development has revealed a crucial and evolutionarily conserved role for the vascular endothelial growth factor (Vegf) signaling pathway in determining endothelial cell fate. However, the genes that dictate venous versus arterial cell fate remain largely unknown.
As Dr. Lawson explains, "Until recently, we really didn't know what the signals were that determined artery and venous identity, or even that this process was governed by genetic signals. It was always thought that circulatory flow and pressure caused a blood vessel to be an artery or a vein. But our work, along with studies in mouse, demonstrates that this identification step is crucial for normal blood vessel formation."
This work by Dr. Lawson and colleagues in Brant Weinstein's lab at the National Institutes of Health (Bethesda, MD) reveals that Plcg1 functions downstream of Vegf in vivo to coax endothelial cells into adopting an arterial fate.
Dr. Lawson and colleagues conducted their studies in zebrafish (an established vertebrate model organism) that were genetically engineered to have fluorescent blood vessels. Since zebrafish embyos are normally transparent, the fluorescing blood vessels enabled the scientists to easily observe vessel formation during development. To identify potential regulators of Vegf signaling, Dr. Lawson and colleagues screened this population of zebrafish for blood vessel defects associated with the loss of Vegf function.
The researchers thus identified "y10": a mutant fish that appeared to lack arteries, but had ostensibly normal veins. Dr. Lawson and colleagues determined that the gene responsible for the y10 mutant phenotype was plcg1. The plcg1 protein (Plcg1) is an intracellular signaling molecule found in a number of vertebrate species, including mammals. While previous work implicated Plcg1 in endothelial cell signaling in vitro, a specific requirement for Plcg1 in arterial development in vivo was, heretofore, unknown.
In addition to providing novel insight into the specification of arterial cell fate during development, these finding illustrate the utility of this transgenic zebrafish system, which the authors expect to be a valuable tool in the further exploration of this developmental pathway.
"I think an important implication of this work is that the signals that drive this process appear to be the same in fish and mammals. For that reason we think it is likely that what we learn about zebrafish blood vessels may help us manipulate the growth of human blood vessels in a variety of disease processes, including diabetes and cancer. The increasing availability of useful genetic tools in zebrafish, such as our blood vessel transgenic line and the soon-to-be-completed genome sequence, will only increase the utility of this model organism to define the signals that drive normal blood vessel development," states Dr. Lawson, who is continuing this work in his own lab at the University of Massachusetts Medical School, where he is an assistant professor of molecular medicine.
Journal
Genes & Development