Summary: The developing brain builds two critical systems at once: the neural communication network and the vascular life-support system. New research identifies a single protein, Adgrl2, that acts like a master architect for both systems.
Through a process called alternative splicing, cells edit the Adgrl2 gene to produce different protein variants. In neurons, the protein helps organize synapses; in brain blood vessel cells (endothelial cells), it helps maintain the blood-brain barrier. When this splicing is disrupted or the “wrong” variant is expressed in the wrong cell type, the balance between neural connectivity and vascular integrity breaks down, causing leaky vessels or dangerous fluid accumulation in the brain.
Key Facts
- Dual-Function Protein: Adgrl2 guides cell recognition and contact formation. It is required for proper synapse organization in neurons and for maintaining endothelial cell junctions in the cerebrovasculature.
- The Splicing Switch: The Adgrl2 gene sequence is the same in all cells, but alternative splicing produces cell type–specific isoforms in neurons and endothelial cells.
- Vascular Integrity: Deleting Adgrl2 specifically from endothelial cells in mice compromises the blood-brain barrier, permitting potentially harmful blood-borne substances to reach neurons.
- Mistaken Identity: Forcing endothelial cells to express the neuronal Adgrl2 isoform causes them to form synapse-like contacts with neurons and over-tighten the barrier, which can disrupt fluid homeostasis and promote hydrocephalus.
- Structural Balance: The study shows that distinct Adgrl2 isoforms are necessary to keep the brain’s signaling network and its vascular plumbing distinct yet properly coordinated.
Source: UCR
The brain’s communication network is built as neurons form contact points called synapses, allowing electrical and chemical signals to pass from one cell to another. Simultaneously, a dense vascular network develops to deliver oxygen and nutrients and to regulate what substances can enter the brain.
Adgrl2 functions as a molecular guide, helping nearby cells identify one another and form the correct types of contacts. In neurons this protein organizes synaptic sites; in the endothelial cells that line brain blood vessels, it helps seal junctions to preserve vascular stability.
Garret R. Anderson at the University of California, Riverside, and his team, led in part by neuroscience graduate student Alexander King, investigated how a single protein can perform distinct roles in different brain cell types.
Published in the Journal of Neuroscience, their experiments show that removing Adgrl2 from endothelial cells in mice caused the cerebrovasculature to lose integrity.
“Normally, brain blood vessels form a selective boundary—the blood-brain barrier—that prevents many blood-borne chemicals from contacting neurons,” Anderson said. “When Adgrl2 is absent in endothelial cells, that barrier becomes leaky. Our results demonstrate that Adgrl2 is essential for maintaining a healthy vascular seal in the brain.”
Although neurons and endothelial cells contain the same Adgrl2 gene, the cells process its RNA differently before translating it into protein. This alternative splicing yields distinct Adgrl2 isoforms tailored to each cell type’s function.
When the researchers forced endothelial cells to express the neuronal Adgrl2 isoform, the vessels began making synapse-like contacts with neurons. “It was as if the endothelial cells switched roles and started trying to join the neural circuitry rather than preserving vascular function,” Anderson explained.
That switch produced an overly restrictive blood-brain barrier. Instead of becoming leaky, the barrier tightened excessively, disrupting fluid exchange between blood and cerebrospinal fluid. This imbalance enlarged brain ventricles and increased the risk of hydrocephalus, a condition characterized by excessive fluid buildup in the brain.
Funding: The study was supported by grants from the Whitehall Foundation and a Regents Faculty Development Grant from the UCR Academic Senate.
The research team included Alexander King, Catherine Garcia, Crisylle Blanton, Anna Chen, and Amna Ahmad (UCR); David Lukacsovich and Csaba Földy (University of Zurich); and Takako Makita (University of South Carolina), alongside Garret R. Anderson.
Key Questions Answered:
A: Because of alternative splicing. The Adgrl2 gene is like a basic recipe whose instructions can be edited. Neurons and endothelial cells use different edits to create different protein variants. If endothelial cells produce the neuronal variant, they begin to behave like neurons rather than maintaining vascular function.
A: A leaky blood-brain barrier allows unwanted molecules and pathogens into the brain, which can trigger neuroinflammation and neuronal damage and contributes to neurodegenerative disease processes.
A: Potentially. Current hydrocephalus treatments are often surgical. Understanding how Adgrl2 controls vascular tightness could guide development of therapies that restore proper blood-brain barrier function and fluid balance without invasive procedures.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The Journal of Neuroscience paper was reviewed in full.
- Additional context was added by editorial staff for clarity.
About this neuroscience and genetics research news
Author: Iqbal Pittalwala
Source: UCR
Contact: Iqbal Pittalwala – UCR
Image: Image credit: 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
Proper development of the central nervous system requires coordinated but distinct programs of neural circuit assembly and vascularization. The cell-adhesion G-protein coupled receptor Adgrl2 sits at the intersection of these processes.
In specific neuronal populations, Adgrl2 localizes to and guides assembly of particular synaptic sites. In non-neuronal brain cells, expression of Adgrl2 is confined to endothelial cells. Using mouse models of both sexes, the authors demonstrate that deleting Adgrl2 selectively from endothelial cells impairs cerebrovascular integrity.
To explain how Adgrl2 can fulfill separate roles in neurons and endothelial cells, the study examined Adgrl2 transcripts across cell types. Single-cell RNA sequencing analysis revealed robust, cell type–specific alternative splicing that produces distinct Adgrl2 isoforms in neurons versus endothelial cells.
When the neuronal isoform of Adgrl2 was expressed in endothelial cells, cerebrovascular properties changed: endothelial cells formed ectopic glutamatergic synaptic contacts and altered cell–cell recognition. Functionally, this switch produced an opposite effect to endothelial Adgrl2 deletion—rather than weakening the barrier, it enhanced barrier tightness to an excessive degree. That over-restriction disrupted blood-to-cerebrospinal fluid homeostasis, enlarged brain ventricles, and increased hydrocephalus risk.
These results indicate that alternative splicing provides isoform-specific Adgrl2 functions that separately govern neural circuit assembly and cerebrovascular homeostasis.