Summary: The developing brain is a construction site where two massive systems, the neural communication network and the vascular life-support system, must be built simultaneously. New research reveals that a single protein named Adgrl2 acts as a master architect for both.
The study shows that through a process called alternative splicing, cells “edit” the Adgrl2 gene to perform different jobs. In neurons, it builds synapses; in blood vessels, it seals the blood-brain barrier. When this “editing” goes wrong, the systems collide, leading to leaky vessels or dangerous fluid buildup.
Key Facts
- Dual-Function Protein: Adgrl2 is a molecular guide that helps cells recognize each other. It is essential for organizing synapses (the junctions between neurons) and maintaining the integrity of endothelial cells (the lining of blood vessels).
- The Splicing Switch: Although the gene is identical in both cell types, neurons and endothelial cells use alternative splicing to create slightly different versions of the protein.
- Vascular Integrity: When researchers removed Adgrl2 specifically from blood vessels, the blood-brain barrier became “leaky,” allowing potentially toxic chemicals from the blood to reach sensitive neurons.
- A Case of Mistaken Identity: When blood vessels were forced to produce the neuronal version of Adgrl2, they behaved like neurons. They formed “synapse-like” contacts with brain cells and over-tightened the barrier, leading to hydrocephalus (fluid buildup in the brain).
- Structural Balance: The study proves that Adgrl2’s specific “flavors” are what keep the brain’s communication and plumbing systems separate but functional.
Source: UCR
The communication network in the developing brain builds when neurons partner up to form contact points called synapses, allowing signals to pass form one cell to another. At the same time, a web of blood vessels builds the brain’s life support system, delivering oxygen and nutrients and controlling what can enter the brain.
The protein Adgrl2 acts as a molecular guide by helping cells recognize one another and form the right connections. In neurons, it helps organize synapses. In cells that line blood vessels in the brain (endothelial cells), it keeps the vessels stable and sealed.
Garret R. Anderson at the University of California, Riverside and his team led by neuroscience graduate student Alexander King, wondered how one protein could manage such different jobs in different cells.
They report in the Journal of Neuroscience that when they removed Adgrl2 specifically from endothelial cells in mice, they found the brain’s blood vessels lost their integrity.
“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, an assistant professor of molecular, cell and systems biology. “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 team found that although the gene for Adgrl2 is the same in neurons and blood vessel cells, the cells can edit the gene’s instructions before turning it into a protein.
“This process, called alternative splicing, allows different cell types to produce slightly different versions of Adgrl2,” Anderson said. “Neurons make one version; endothelial cells make another.”
Next, forcing endothelial cells to produce the neuronal version of Adgrl2, the researchers found the blood vessel cells formed synapse-like contacts with neurons.
“It was as if the cells were trying to join the brain’s communication network instead of maintaining the vascular system,” Anderson said.
“The blood vessels became overly restrictive and the barrier that normally regulates what passes from the blood into the brain tightened, disrupting the balance between the blood and the brain. This can increase the risk of hydrocephalus, a condition where excess fluid builds up in the brain.”
Funding: The research was funded by grants from the Whitehall Foundation, and Regents Faculty Development Grant from the UCR Academic Senate.
Anderson was joined in the study by Alexander King, Catherine Garcia, Crisylle Blanton, Anna Chen, and Amna Ahmad of UCR; David Lukacsovich and Csaba Földy of the University of Zurich; and Takako Makita of the University of South Carolina.
Key Questions Answered:
A: Because of “alternative splicing.” Think of the Adgrl2 gene like a standard recipe. Neurons follow the recipe to make a “cake,” while blood vessels edit the same recipe to make “bread.” This study shows that if the blood vessels accidentally make the “cake” version, they start acting like neurons and stop acting like a pipe.
A: The blood-brain barrier is like a highly selective bouncer at a club. If it’s leaky, “uninvited” chemicals and pathogens can enter the brain. This can lead to neuroinflammation, cell death, and is a major factor in many neurodegenerative diseases.
A: Yes. Hydrocephalus (water on the brain) is often treated with surgery to install a shunt. By understanding that Adgrl2 controls the “tightness” of the vascular system, scientists might eventually develop drug therapies that rebalance the blood-brain barrier without needing invasive surgery.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this neuroscience and genetics research news
Author: Iqbal Pittalwala
Source: UCR
Contact: Iqbal Pittalwala – UCR
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Endothelial Adgrl2 Expression and Alternative Splicing Controls the Cerebrovasculature” by Alexander King, Catherine Garcia, Crisylle Blanton, Anna Chen, Amna Ahmad, David Lukacsovich, Csaba Földy, Takako Makita and Garret R. Anderson. Journal of Neuroscience
DOI:10.1523/JNEUROSCI.0019-26.2026
Abstract
Endothelial Adgrl2 Expression and Alternative Splicing Controls the Cerebrovasculature
Central nervous system development requires parallel but interrelated processes of neural circuit assembly and vascularization. Intersecting between these two processes is the cell-adhesion G-protein coupled receptor Adgrl2.
In select neuronal populations, Adgrl2 is localized and control the assembly of specific synaptic sites. In non-neuronal brain cells, Adgrl2 is restricted in expression to endothelial cells. Testing for Adgrl2 function in these cells in mice (of either sex), here we find that endothelial cell-specific Adgrl2 deletion results in an impairment in cerebrovascular integrity.
To understand how it might be possible for Adgrl2 to function independently in neuronal and endothelial contexts, we surveyed Adgrl2 transcripts within these cell classes.
By analyzing single-cell RNA sequencing datasets, we find that Adgrl2 mRNA is subject to robust cell type-specific alternative splicing that results in distinct isoforms being produced in neurons compared with endothelial cells.
To probe the functional significance of this alternative splicing, we forced expression of the neuronal isoform of Adgrl2 in endothelial cells. This resulted in altered cerebrovascular properties including the formation of ectopic glutamatergic synaptic contacts onto endothelial cells, indicating alterations in the cell–cell recognition process.
Functionally, in direct contrast to endothelial Adgrl2 deletion, this genetic expression switch instead enhances blood–brain barrier integrity. This overly restrictive cerebrovascular function results in dysregulation of blood to cerebrospinal fluid homeostasis, enlargement of brain ventricles, and a higher risk of hydrocephalus.
Thus, alternative splicing serves as a cell type-specific mechanism that provides isoform-specific Adgrl2 for discerning functions controlling neural circuit assembly and cerebrovascular homeostasis.
