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A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding.

ABSTRACT: 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 ADGRG1/GPR56 controls multiple aspects of brain development in a cell type-specific manner: In neural progenitor cells, GPR56 regulates cortical lamination, whereas in oligodendrocyte progenitor cells, GPR56 controls developmental myelination and myelin repair. Here, we show that microglial GPR56 maintains appropriate synaptic numbers in several brain regions in a time- and circuit-dependent fashion. Phosphatidylserine (PS) on presynaptic elements binds GPR56 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 GPR56 is selectively required for microglia-mediated synaptic pruning. Our present data provide a ligand- and isoform-specific mechanism underlying microglial GPR56-mediated synapse pruning in the context of complex neurodevelopmental processes.

SUBMITTER: Li T

PROVIDER: S-EPMC7429740 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A splicing isoform of GPR56 mediates microglial synaptic refinement via phosphatidylserine binding

Project description: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 ADGRG1/GPR56 controls multiple aspects of brain development in a cell type-specific manner: in neural progenitor cells, GPR56 regulates cortical lamination, whereas in oligodendrocyte progenitor cells, GPR56 controls developmental myelination and myelin repair. Here, we show that microglial GPR56 maintains appropriate synaptic numbers in several brain regions in a time- and circuit-dependent fashion. Phosphatidylserine (PS) on pre-synaptic elements binds GPR56 in a domain-specific manner, and microglia-specific deletion of Gpr56 leads to increased synapses as a result of reduced microglial engulfment of PS+ pre-synaptic inputs. Remarkably, a particular alternatively spliced isoform of GPR56 is selectively required for microglia-mediated synaptic pruning. Our present data provide a ligand- and isoform-specific mechanism underlying microglial GPR56-mediated synapse pruning in the context of complex neurodevelopmental processes.

| S-SCDT-EMBOJ-2019-104136 | biostudies-other

Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice.

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-12-12 | GSE218428 | GEO

Local externalization of phosphatidylserine mediates developmental synaptic pruning by microglia.

Project description:Neuronal circuit assembly requires the fine balance between synapse formation and elimination. Microglia, through the elimination of supernumerary synapses, have an established role in this process. While the microglial receptor TREM2 and the soluble complement proteins C1q and C3 are recognized as key players, the neuronal molecular components that specify synapses to be eliminated are still undefined. Here, we show that exposed phosphatidylserine (PS) represents a neuronal "eat-me" signal involved in microglial-mediated pruning. In hippocampal neuron and microglia co-cultures, synapse elimination can be partially prevented by blocking accessibility of exposed PS using Annexin V or through microglial loss of TREM2. In vivo, PS exposure at both hippocampal and retinogeniculate synapses and engulfment of PS-labeled material by microglia occurs during established developmental periods of microglial-mediated synapse elimination. Mice deficient in C1q, which fail to properly refine retinogeniculate connections, have elevated presynaptic PS exposure and reduced PS engulfment by microglia. These data provide mechanistic insight into microglial-mediated synapse pruning and identify a novel role of developmentally regulated neuronal PS exposure that is common among developing brain structures.

| S-EPMC7429741 | biostudies-literature

Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice (ATACseq)

Project description:To determine the direct effect of IL-33 on microglial gene expression, we have bulk ATAC-sequenced cortical microglia 4 hours after IL-33 or vehicle i.c.v. injection.

2022-12-12 | GSE218424 | GEO

Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice (scRNAseq)

Project description:To determine the effect of IL-33 on microglial gene expression, we have scRNA-sequenced cortical microglia from ST2KO and WT mice 4 hours after IL-33 or vehicle i.c.v. injection.

2022-12-12 | GSE218427 | GEO

Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice (FOS ChIP-seq)

Project description:To determine whether FOS is involved in the IL-33 microglial gene expression response, we have FOS ChIP-sequenced cortical microglia 4 hours after IL-33 i.c.v. injection.

2022-12-12 | GSE218425 | GEO

Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice (H3K27ac ChIP-seq)

Project description:To determine the direct effect of IL-33 on microglial gene expression, we have H3K27ac ChIP-sequenced cortical microglia 4 hours after IL-33 or vehicle i.c.v. injection.

2022-12-12 | GSE218426 | GEO

Microglial pattern recognition via IL-33 promotes synaptic refinement in developing corticothalamic circuits in mice (bulk RNA-seq)

Project description:To determine the direct effect of IL-33 on microglial gene expression, we have bulk RNA-sequenced cortical microglia 4 hours after IL-33 or vehicle i.c.v. injection.

2022-12-12 | GSE218369 | GEO

Microglial transglutaminase-2 drives myelination and myelin repair via GPR56/ADGRG1 in oligodendrocyte precursor cells.

Project description:In the central nervous system (CNS), myelin formation and repair are regulated by oligodendrocyte (OL) lineage cells, which sense and integrate signals from their environment, including from other glial cells and the extracellular matrix (ECM). The signaling pathways that coordinate this complex communication, however, remain poorly understood. The adhesion G protein-coupled receptor ADGRG1 (also known as GPR56) is an evolutionarily conserved regulator of OL development in humans, mice, and zebrafish, although its activating ligand for OL lineage cells is unknown. Here, we report that microglia-derived transglutaminase-2 (TG2) signals to ADGRG1 on OL precursor cells (OPCs) in the presence of the ECM protein laminin and that TG2/laminin-dependent activation of ADGRG1 promotes OPC proliferation. Signaling by TG2/laminin to ADGRG1 on OPCs additionally improves remyelination in two murine models of demyelination. These findings identify a novel glia-to-glia signaling pathway that promotes myelin formation and repair, and suggest new strategies to enhance remyelination.

| S-EPMC5980231 | biostudies-literature

Vitamin A metabolite, all-trans-retinoic acid, mediates alternative splicing of protein kinase C deltaVIII (PKCdeltaVIII) isoform via splicing factor SC35.

Project description:Vitamin A metabolite, all-trans-retinoic acid (RA), induces cell growth, differentiation, and apoptosis and has an emerging role in gene regulation and alternative splicing events. Protein kinase Cdelta (PKCdelta), a serine/threonine kinase, has a role in cell proliferation, differentiation, and apoptosis. We reported an alternatively spliced variant of human PKCdelta, PKCdeltaVIII that functions as a pro-survival protein (1). RA regulates the splicing and expression of PKCdeltaVIII via utilization of a downstream 5' splice site of exon 10 on PKCdelta pre-mRNA. Here, we further elucidate the molecular mechanisms involved in RA regulation of alternative splicing of PKCdeltaVIII mRNA. Overexpression and knockdown of the splicing factor SC35 (i.e. SRp30b) indicated that it is involved in PKCdeltaVIII alternative splicing. To identify the cis-elements involved in 5' splice site selection we cloned a minigene, which included PKCdelta exon 10 and its flanking introns in the pSPL3 splicing vector. Alternative 5' splice site utilization in the minigene was promoted by RA. Further, co-transfection of SC35 with PKCdelta minigene promoted selection of 5' splice site II. Mutation of the SC35 binding site in the PKCdelta minigene abolished RA-mediated utilization of 5' splice splice II. RNA binding assays demonstrated that the enhancer element downstream of PKCdelta exon 10 is a SC35 cis-element. We conclude that SC35 is pivotal in RA-mediated PKCdelta pre-mRNA alternative splicing. This study demonstrates how a nutrient, vitamin A, via its metabolite RA, regulates alternative splicing and thereby gene expression of the pro-survival protein PKCdeltaVIII.

| S-EPMC2923993 | biostudies-literature

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