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

Li, Tao; Chiou, Brian; Gilman, Casey K.; Luo, Rong; Koshi, Tatsuhiro; Yu, Diankun; Oak, Hayeon C; Giera, Stefanie; Johnson-Venkatesh, Erin; Muthukumar, Allie K.; Stevens, Beth; Umemori, Hisashi; Piao, Xiangshu

doi:10.15252/embj.2019104136

Cited by 106 publications

(152 citation statements)

References 102 publications

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“…ADGRG1 encodes the adhesion family GPCR GPR56 (28), which is more widely expressed in the CNS and has been linked in neuronal precursors with cortical lamination and in oligodendrocyte precursors with proliferation (29). Abundant presence of GPR56 on human microglia (4) and regulation of synaptic refinement through a mouse GPR56 splicing isoform (30) have been reported only recently. Obviously, ADGRG1 expression not only distinguishes microglia from other macrophages but also fades out in response to minor changes in the microenvironment, stressing its value as indicator of microglia homeostasis.…”

Section: Discussionmentioning

confidence: 99%

GPCRomics of Homeostatic and Disease-Associated Human Microglia

et al. 2021

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G-protein-coupled receptors (GPCRs) are critical sensors affecting the state of eukaryotic cells. To get systematic insight into the GPCRome of microglia, we analyzed publicly available RNA-sequencing data of bulk and single cells obtained from human and mouse brains. We identified 17 rhodopsin and adhesion family GPCRs robustly expressed in microglia from human brains, including the homeostasis-associated genes CX3CR1, GPR34, GPR183, P2RY12, P2RY13, and ADGRG1. Expression of these microglial core genes was lost upon culture of isolated cells ex vivo but could be acquired by human induced pluripotent stem cell (iPSC)-derived microglial precursors transplanted into mouse brains. CXCR4 and PTGER4 were higher expressed in subcortical white matter compared to cortical grey matter microglia, and ADGRG1 was downregulated in microglia obtained from normal-appearing white and grey matter tissue of multiple sclerosis (MS) brains. Single-cell RNA sequencing of microglia from active lesions, obtained early during MS, revealed downregulation of homeostasis-associated GPCR genes and upregulation of CXCR4 expression in a small subset of MS-associated lesional microglia. Functional presence of low levels of CXCR4 on human microglia was confirmed using flow cytometry and transwell migration towards SDF-1. Microglia abundantly expressed the GPCR down-stream signaling mediator genes GNAI2 (αi2), GNAS (αs), and GNA13 (α13), the latter particularly in white matter. Drugs against several microglia GPCRs are available to target microglia in brain diseases. In conclusion, transcriptome profiling allowed us to identify expression of GPCRs that may contribute to brain (patho)physiology and have diagnostic and therapeutic potential in human microglia.

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Section: Discussionmentioning

confidence: 99%

GPCRomics of Homeostatic and Disease-Associated Human Microglia

et al. 2021

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“…This may imply selective expression of a cue. Intriguingly, a recent preprint identified phosphatidylserine (PS), a known eat-me cue at synapses (Li et al, 2020;Park et al, 2020;Scott-Hewitt et al, 2020), as a likely cue for developmental myelin phagocytosis (Djannatian et al, 2021). Similar to synapse elimination, the cues that direct myelin phagocytosis may vary between brain regions (Gunner et al, 2019).…”

Section: Microglial Interactions With Oligodendrocyte Lineage Cells and Myelinmentioning

confidence: 99%

Glial Cells Promote Myelin Formation and Elimination

Hughes

2021

Front. Cell Dev. Biol.

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Building a functional nervous system requires the coordinated actions of many glial cells. In the vertebrate central nervous system (CNS), oligodendrocytes myelinate neuronal axons to increase conduction velocity and provide trophic support. Myelination can be modified by local signaling at the axon-myelin interface, potentially adapting sheaths to support the metabolic needs and physiology of individual neurons. However, neurons and oligodendrocytes are not wholly responsible for crafting the myelination patterns seen in vivo. Other cell types of the CNS, including microglia and astrocytes, modify myelination. In this review, I cover the contributions of non-neuronal, non-oligodendroglial cells to the formation, maintenance, and pruning of myelin sheaths. I address ways that these cell types interact with the oligodendrocyte lineage throughout development to modify myelination. Additionally, I discuss mechanisms by which these cells may indirectly tune myelination by regulating neuronal activity. Understanding how glial-glial interactions regulate myelination is essential for understanding how the brain functions as a whole and for developing strategies to repair myelin in disease.

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“…To investigate whether microglial Adgrg1 plays a role in this process, we crossed Adgrg1 fl/fl mice with a microglia-specific Cre driver, Cx3cr1-Cre. We have recently showed that this mouse line mediates Cre recombination in high specificity and efficiency (T. Li et al, 2020). Black-Gold staining at P21 in this model showed no difference in myelin intensity between the control and Adgrg1 fl/fl ; Cx3cr1-Cre mice (Figure 3a,b).…”

Section: Microgliamentioning

confidence: 75%

Cell type‐specific evaluation of ADGRG1/GPR56 function in developmental central nervous system myelination

Chiou

Gao

Giera

et al. 2020

Glia

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Myelination of axons in the central nervous system (CNS) is a concerted effort between many cell types, resulting in significant cross-talk and communication among cells. Adhesion G protein-coupled receptor ADGRG1 (GPR56) is expressed in all major glial cells and regulates a wide variety of physiological processes by mediating cell-cell and cell-matrix communications. Previous literature has demonstrated the requirement of ADGRG1 in oligodendrocyte precursor cells (OPCs) during developmental myelination. However, it is unknown if ADGRG1 is responsible for myelin formation in a cell-type-specific manner. To that end, here we profiled myelin status in response to deletion of Adgrg1 specifically in OPCs, microglia, astrocytes, and neurons. Interestingly, we find that knocking out Adgrg1 in OPCs significantly decreases OPC proliferation and reduced number of myelinated axons. However, deleting Adgrg1 in microglia, astrocytes, and neurons does not impact developmental myelination. These data support an autonomous functional role for Adgrg1 in OPCs related to myelination.

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

Cited by 106 publications

References 102 publications

GPCRomics of Homeostatic and Disease-Associated Human Microglia

GPCRomics of Homeostatic and Disease-Associated Human Microglia

Glial Cells Promote Myelin Formation and Elimination

Cell type‐specific evaluation of ADGRG1/GPR56 function in developmental central nervous system myelination

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