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A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding
Author(s) -
Li Tao,
Chiou Brian,
Gilman Casey K,
Luo Rong,
Koshi Tatsuhiro,
Yu Diankun,
Oak Hayeon C,
Giera Stefanie,
JohnsonVenkatesh Erin,
Muthukumar Allie K,
Stevens Beth,
Umemori Hisashi,
Piao Xianhua
Publication year - 2020
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.2019104136
Subject(s) - biology , phosphatidylserine , gene isoform , alternative splicing , rna splicing , microbiology and biotechnology , biochemistry , gene , rna , phospholipid , membrane
Developmental synaptic remodeling is important for the formation of precise neural circuitry, and its disruption has been linked to neurodevelopmental disorders such as autism and schizophrenia. Microglia prune synapses, but integration of this synapse pruning with overlapping and concurrent neurodevelopmental processes, remains elusive. Adhesion G protein‐coupled receptor ADGRG 1/ GPR 56 controls multiple aspects of brain development in a cell type‐specific manner: In neural progenitor cells, GPR 56 regulates cortical lamination, whereas in oligodendrocyte progenitor cells, GPR 56 controls developmental myelination and myelin repair. Here, we show that microglial GPR 56 maintains appropriate synaptic numbers in several brain regions in a time‐ and circuit‐dependent fashion. Phosphatidylserine ( PS ) on presynaptic elements binds GPR 56 in a domain‐specific manner, and microglia‐specific deletion of Gpr56 leads to increased synapses as a result of reduced microglial engulfment of PS + presynaptic inputs. Remarkably, a particular alternatively spliced isoform of GPR 56 is selectively required for microglia‐mediated synaptic pruning. Our present data provide a ligand‐ and isoform‐specific mechanism underlying microglial GPR 56‐mediated synapse pruning in the context of complex neurodevelopmental processes.