Endothelial Adgrl2 Expression and Alternative Splicing Controls the Cerebrovasculature.

Area of Science:

• Neuroscience
• Developmental Biology
• Molecular Biology

Background:

• Brain development involves coordinated neural circuit assembly and vascularization.
• The cell-adhesion G-protein coupled receptor Adgrl2 is implicated in both processes.
• Adgrl2 expression is found in specific neuronal populations and brain endothelial cells.

Purpose of the Study:

• To investigate the distinct functions of Adgrl2 in neurons and endothelial cells.
• To explore the role of cell type-specific alternative splicing of Adgrl2.
• To understand how Adgrl2 contributes to cerebrovascular integrity and neural development.

Main Methods:

• Endothelial cell-specific deletion of Adgrl2 in mice.
• Analysis of Adgrl2 transcripts using single-cell RNA sequencing.
• Forced expression of neuronal Adgrl2 isoform in endothelial cells.

Main Results:

• Endothelial Adgrl2 deletion impairs cerebrovascular integrity.
• Cell type-specific alternative splicing generates distinct Adgrl2 isoforms in neurons and endothelial cells.
• Forcing neuronal Adgrl2 expression in endothelial cells leads to ectopic synapses and enhanced blood-brain barrier integrity, causing hydrocephalus.

Conclusions:

• Alternative splicing of Adgrl2 provides isoform-specific functions critical for neural circuit assembly and cerebrovascular homeostasis.
• Adgrl2 acts as a molecular switch, with different isoforms mediating distinct cellular recognition processes.
• This study highlights alternative splicing as a key mechanism for gene functional diversification during brain development.