Adgrl2 Protein Shapes Brain Health by Controlling Specialized Cell Functions

The development of the human brain requires the precise coordination of two critical systems: the neuronal communication network, built by synapses, and the vascular system, which provides essential nutrients and oxygen. A protein known as Adgrl2 serves as a molecular guide in this process, ensuring that cells identify one another and establish appropriate connections. In neurons, Adgrl2 is responsible for organizing synapses. Simultaneously, in the endothelial cells that form the lining of brain blood vessels, the protein acts to keep those vessels stable and sealed.

A team led by Garret R. Anderson at the University of California, Riverside recently investigated how a single protein manages these distinct functions in different cell types. Their findings, published in the Journal of Neuroscience, reveal that Adgrl2 is essential for the integrity of the brain’s blood vessels. When the researchers experimentally removed Adgrl2 from endothelial cells in mice, the vascular system lost its stability.

“Normally, brain blood vessels form a specialized unit known as the blood-brain barrier, which do not allow certain chemicals in the blood to come in contact with neurons in the brain,” said Anderson. “Without Adgrl2, we found that the vessels became leaky and allowed these chemicals to get through. This shows Adgrl2 is essential for maintaining a healthy vascular system in the brain.”

The researchers discovered that while the genetic code for Adgrl2 is identical in both neurons and vascular cells, the cells employ a mechanism called alternative splicing to edit the gene’s instructions. This editing process results in two distinct versions of the Adgrl2 protein, tailored to the specific needs of each cell type. When the team forced endothelial cells to produce the version of the protein typically found in neurons, the blood vessel cells attempted to participate in the brain’s communication network instead of maintaining vascular structure.

This modification caused the blood vessels to become overly restrictive, tightening the barrier that regulates passage from the blood to the brain. This disruption in the balance between the vascular and neuronal systems is concerning, as it can potentially increase the risk of hydrocephalus, a condition characterized by the buildup of excess fluid within the brain. Ultimately, the study highlights the complexity of cellular development and the functional diversity enabled by alternative splicing within the developing brain.