GPR124 protein controls growth of blood vessels into brains

November 17, 2017

Kuo and Kuhnert next overexpressed GPR124 in the mice and followed their development. While the mice at first seemed normal, they began to develop large tangles of blood vessels in their forebrains as they aged. After about one year, nearly 70 percent of the mice displayed this kind of abnormal hypervasculature - but only in their brains. The results show that the action of GPR124 is highly specific for the central nervous system.

Still, the identity of the receptor's ligand remains a mystery. Kuo and his colleagues teamed up with researchers from Stanford's School of Engineering to narrow down the options. They used a microfluidic chamber - a technique that, among other things, allows the analysis of single-cell behavior - specially constructed by graduate student Amir Shamloo to investigate how mouse endothelial cells expressing GPR124 reacted to cells from different parts of the brain. Shamloo works in the lab of Sarah Heilshorn, PhD, assistant professor in materials science and engineering.

The researchers placed the cells in the middle of the chamber, and filled the channels on either side with these extracts from the forebrain - where the receptor's effects seem to be concentrated - or the hindbrain, where the receptor is not essential. They found that the endothelial cells only migrated toward the extract from the forebrain, much like the blood vessels grow toward and penetrate the embryonic brain during development.

"This was a key turning point," Kuo said of the collaboration. "We struggled for years to model the action of this receptor in vitro, but we couldn't do it without these microfluidic chambers."

In the future, the researchers plan to use mice in which they can toggle the expression of GPR124 on and off at will to examine its role in brain tumor development and stroke. They also hope to learn more about whether GPR124 is involved in the formation of the blood-brain barrier.

"There are a tremendous number of disorders that could be affected by GPR124 expression," said Kuo. "We're excited to begin those studies."

Source: Stanford University Medical Center