Summary: The developing brain builds two essential systems at once: a neural network that passes messages between neurons and a vascular network that supplies oxygen and blocks harmful substances. New research identifies a single protein, Adgrl2, as a shared molecular architect for both systems. The study shows that alternative splicing produces distinct Adgrl2 isoforms in different cell types, allowing one gene to support separate functions in neurons and blood‑vessel cells. When this splicing is disrupted, the balance between communication and vascular integrity breaks down, producing either leaky vessels or excessive barrier tightening with harmful consequences.
Neural circuits assemble as neurons form synapses—specialized contact points that transfer electrical and chemical signals. At the same time, a network of endothelial cells forms blood vessels that create the blood‑brain barrier (BBB), a selective interface that controls which blood-borne molecules can access brain tissue. The protein Adgrl2 is a cell‑adhesion G‑protein‑coupled receptor that helps cells recognize appropriate partners during these parallel construction processes.
Researchers led by Garret R. Anderson at the University of California, Riverside, and neuroscience graduate student Alexander King investigated how a single gene could perform different tasks in distinct cell types. Their experiments in mice reveal that endothelial expression of Adgrl2 is critical for cerebrovascular integrity, and that neurons and endothelial cells use alternative splicing to produce different functional versions of the protein.
Key Facts
- Dual‑purpose protein: Adgrl2 guides cell–cell recognition. In neurons it organizes synapses; in endothelial cells it helps maintain vessel stability and the blood‑brain barrier.
- Alternative splicing creates specificity: The Adgrl2 gene is identical across cell types, but neurons and endothelial cells splice the transcript differently, producing distinct isoforms tailored to each cell’s role.
- Vascular integrity depends on Adgrl2: Selective deletion of Adgrl2 from endothelial cells in mice made brain vessels leaky, allowing blood-borne chemicals to reach vulnerable neurons.
- Mistaken identity has severe effects: Forcing endothelial cells to express the neuronal Adgrl2 isoform caused those cells to form synapse‑like contacts with neurons and over-tighten the blood‑brain barrier, disrupting fluid balance and increasing the risk of hydrocephalus.
- Balance of structure and function: The study demonstrates that cell type–specific isoforms of Adgrl2 keep the brain’s communication network and vascular system distinct yet coordinated.
Anderson and colleagues used genetic tools in mice to test endothelial Adgrl2 function. When the protein was removed specifically from brain endothelial cells, the blood‑brain barrier lost selectivity and became permeable to molecules that are normally excluded from neural tissue. This finding establishes endothelial Adgrl2 as essential for maintaining a healthy cerebrovasculature.
To probe how Adgrl2 can play different roles, the team analyzed single‑cell RNA sequencing datasets. They found robust, cell type–specific alternative splicing of Adgrl2 transcripts: neurons predominantly express one isoform, while endothelial cells predominantly express another. To test the functional consequences, researchers engineered endothelial cells to express the neuronal Adgrl2 isoform. These vessels began to acquire neuronal-like properties, forming glutamatergic, synapse‑like contacts with nearby neurons.
Rather than causing leakiness, this forced expression produced an overly restrictive barrier. The tightened cerebrovascular interface disturbed blood–cerebrospinal fluid homeostasis, enlarged brain ventricles, and raised the risk of hydrocephalus—demonstrating that the correct Adgrl2 isoform must be present in each cell type to preserve the proper balance between permeability and protection.
Funding: The research was supported by grants from the Whitehall Foundation and a Regents Faculty Development Grant from the UCR Academic Senate.
Study contributors include Alexander King, Catherine Garcia, Crisylle Blanton, Anna Chen, and Amna Ahmad (UCR); David Lukacsovich and Csaba Földy (University of Zurich); Takako Makita (University of South Carolina); and Garret R. Anderson (UCR).
Key Questions Answered:
A: Because of alternative splicing. Cells edit the Adgrl2 transcript to produce distinct isoforms. Neurons produce the neuronal isoform that promotes synapse assembly; endothelial cells produce a different isoform that promotes vascular stability. When endothelial cells accidentally express the neuronal isoform, they begin to behave like neurons, disrupting vascular function.
A: A leaky BBB allows unwanted chemicals and pathogens into the brain, which can trigger neuroinflammation, neuronal damage, and contribute to neurodegenerative processes. Maintaining barrier integrity is critical for brain health.
A: Potentially. Current hydrocephalus treatments are typically surgical. Understanding how Adgrl2 isoforms regulate barrier tightness may point to pharmacological strategies that rebalance cerebrovascular function and fluid homeostasis without invasive procedures.
Editorial Notes:
- This summary was edited by an experienced neuroscience editor.
- The original journal paper was reviewed in full by staff.
About this research
Author: Iqbal Pittalwala
Source: UCR
Contact: Iqbal Pittalwala, UCR
Image credit: Neuroscience News
Original research (open access): Endothelial Adgrl2 Expression and Alternative Splicing Controls the Cerebrovasculature. 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 coordinated but separate processes of neural circuit assembly and vascularization. The cell‑adhesion G‑protein‑coupled receptor Adgrl2 sits at the intersection of these processes. In certain neuronal populations, Adgrl2 localizes to specific synaptic sites and controls their assembly. In the non‑neuronal brain, Adgrl2 expression is largely restricted to endothelial cells. Endothelial‑specific deletion of Adgrl2 in mice impairs cerebrovascular integrity.
Single‑cell transcriptomic analysis reveals robust, cell type–specific alternative splicing of Adgrl2, producing distinct isoforms in neurons versus endothelial cells. Forced expression of the neuronal Adgrl2 isoform in endothelial cells produces ectopic glutamatergic synaptic contacts on vessels and alters cerebrovascular properties. In contrast to endothelial deletion, this expression switch strengthens the blood‑brain barrier excessively, disrupting blood–cerebrospinal fluid balance, enlarging ventricles, and increasing hydrocephalus risk. Thus, alternative splicing provides isoform‑specific Adgrl2 functions necessary for both neural circuit assembly and cerebrovascular homeostasis.