The investigators also showed the Coup-TFII gene is essential to the process. The Coup-TFII protein binds to the promoter region of the Prox1 gene. The binding switches on production of the Prox1 protein that is required to create and maintain the lymphatic system. The newer research builds on that earlier work from Oliver's laboratory. The latest study focused on the lymphovenous valves. These valves are found at just two locations in the body, on either side of the chest just under the clavicle bone where the lymphatic vessels intersect with the subclavian and internal jugular veins.
Working in mice, investigators discovered that these lymphovenous valves form from a newly identified subtype of endothelial cell found in developing veins. Like the LECs that form the lymphatic system, the newly identified endothelial cells make Prox1. But while the LECs leave the veins and migrate throughout the body, these endothelial cells stay put to form the lymphovenous valves.
Researchers demonstrated the process requires two copies of the Prox1 gene. That ensures adequate levels of the Coup-TFII-Prox1 complex and with it enough Prox1 to build and maintain the lymphatic system. Mice engineered to carry a single copy of Prox1 either did not survive or were born without lymphovenous and venous valves.
"If you have only one copy of Prox1 you are going to have a reduction in the Coup-TFII Prox1 complex and so a dramatic reduction in the number of cells available to build the lymphatic system. That explains the defects we see," Srinivasan said.
|Contact: Summer Freeman|
St. Jude Children's Research Hospital