GPR56 S4 variant is required for microglia‐mediated synaptic pruning

ADGRG1 (also called GPR56) plays critical roles in brain development and wiring, including cortical lamination, central nervous system (CNS) myelination, and developmental synaptic refinement. However, the underlying mechanism(s) in mediating such diverse functions is not fully understood. Here, we...

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Bibliographic Details
Published in:Glia 2023-03, Vol.71 (3), p.560-570
Main Authors: Li, Tao, Luo, Rong, Schmidt, Rachael, D'Alessandro, Nicholas, Kishore, Priya, Zhu, Beika, Yu, Diankun, Piao, Xianhua
Format: Article
Language:English
Subjects:
Alternative splicing
Animals
Central nervous system
CRISPR
GPR56
Lamination
Mice
Mice, Transgenic
Microglia
Myelination
Phenotypes
phosphatidylserine
Protein Isoforms
Pruning
Receptors, G-Protein-Coupled - genetics
Splicing
Synapses
synaptic pruning
Transgenic mice
Wiring
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Summary:ADGRG1 (also called GPR56) plays critical roles in brain development and wiring, including cortical lamination, central nervous system (CNS) myelination, and developmental synaptic refinement. However, the underlying mechanism(s) in mediating such diverse functions is not fully understood. Here, we investigate the function of one specific alternative splicing isoform, the GPR56 splice variant 4 (S4), to test the hypothesis that alternative splicing variants of GPR56 in part support its different functions. We created a new transgenic mouse line, Gpr56∆S4, using CRISPR/Cas9, in which GPR56 S4 was deleted. Detailed phenotype analyses show that Gpr56∆S4 mice manifest no deficits in cortical architecture and CNS myelination compared to controls. Excitingly, they present significantly increased synapse densities, decreased synapse engulfment by microglia, and impaired eye‐segregation. Taken together, our findings support that the GPR56 S4 variant is dispensable for cortical development and CNS myelination but is essential for microglia‐mediated synaptic pruning. Main Points GPR56 S4 isoform is dispensable for cortical lamination and myelination, but required for microgliamediated synaptic pruning.
ISSN:0894-1491
1098-1136
DOI:10.1002/glia.24293