The pathway these molecules make up during vascular development has not been looked at before, says Stainier. It offers a new target for therapeutic strategies.
The birc2 gene belongs to a family of proteins that control the balance between cell survival and cell death (apoptosis). A cell induces apoptosis when it detects that it is irreparably damaged. The integrity of the blood vessel wall is determined by a dynamic balance between endothelial cell survival and apoptosis.
The scientists started the investigation by examining zebrafish with unusual physical characteristics and working to identify the mutated genes that were responsible for the traits.
We began with a genetic mutant that displayed vascular hemorrhage associated with vascular defects, and soon proved that the mutant had a defective birc2 gene, says Santoro. Without the birc2 gene, hemorrhage and blood pooling occurred, resulting in vascular regression and cell death.
Next, through a series of genomic analyses and biochemical studies, the team discovered the critical role of birc2 and TNF in blood vessel health in the zebrafish embryo. They showed that birc2 is needed for the formation of the tumor necrosis factor receptor complex 1, a group of proteins and peptides that activate cell survival by initiating signals. Tumor necrosis factor promotes activation of NF-kB, a protein complex transcription factor involved in the transfer of genetic information. Further tests proved the existence of a genetic link between the birc2/NF-kB pathway, and that it is critical for vascular health and endothelial cell survival.
Studies on vascular development are important so that we can better understand
|Contact: Jennifer O'Brien|
University of California - San Francisco