Endothelial Adgrl2 expression and alternative splicing controls the cerebrovasculature

King, A.; Garcia, C.; Blanton, C.; Chen, A.; Ahmad, A.; Lukacsovich, D.; Foldy, C.; Makita, T.; Anderson, G. R.

doi:10.1101/2025.10.24.682442

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bioRxiv · 10.1101/2025.10.24.682442

Endothelial Adgrl2 expression and alternative splicing controls the cerebrovasculature

King, A.·Garcia, C.·Blanton, C.·Chen, A.·Ahmad, A.·Lukacsovich, D.·Foldy, C.·Makita, T.·Anderson, G. R.

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Abstract

Central nervous system development requires parallel but interrelated processes of neural circuit assembly and vascularization. Intersecting between these two processes, the cell-adhesion G-protein coupled receptor Adgrl2 is expressed in select neuron populations where it has been found to localize and control the assembly of specific synaptic sites. Further, Adgrl2 is found to be expressed in select non-neuronal brain cells, where it is restricted to endothelial cells. Testing for Adgrl2 function in these cells, 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 analyzed single-cell RNA sequencing datasets for differences in transcriptional identity between these cell classes. Doing so, we find that expression of Adgrl2 mRNA is subject to robust cell type-specific alternative splicing, resulting in distinct isoforms being produced in neurons compared to endothelial cells. Investigating the functional implication of this cell type-specific alternative splicing, we find that forced expression of the neuronal isoform of Adgrl2 in endothelial cells leads to alterations in cerebrovascular properties. Morphologically, endothelial cells with the non-native neuronal Adgrl2 isoform induce 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. As such, alternative splicing serves as a cell type specific mechanism that provides isoform specific Adgrl2 for discerning functions controlling neural circuit assembly and cerebrovascular homeostasis.

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King, A., Garcia, C., Blanton, C., Chen, A., Ahmad, A., Lukacsovich, D., Foldy, C., Makita, T., Anderson, G. R.. 2025-10-24. Endothelial Adgrl2 expression and alternative splicing controls the cerebrovasculature. https://doi.org/10.1101/2025.10.24.682442

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