Prostaglandin D2 synthase/GPR44: a signaling axis in PNS myelination

Trimarco, Amelia; Forese, Maria Grazia; Alfieri, Valentina; Lucente, Alessandra; Brambilla, Paola; Dina, Giorgia; Pieragostino, Damiana; Sacchetta, Paolo; Urade, Yoshihiro; Boizet-Bonhoure, Brigitte; Boneschi, Filippo Martinelli; Quattrini, Angelo; Taveggia, Carla

doi:10.1038/nn.3857

Cited by 70 publications

(88 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies by Foran and Peterson (1992) also reported that b-galactosidase expressed under the promoter of myelin basic protein gene was first expressed by the oligodendrocytes in the ventral spinal cord only 1 day prior to birth in mice (Foran and Peterson, 1992). Recent studies of Trimarco et al (2014) indicated that prostaglandin D 2 is important in myelination of neuronal, glial, and oligodendrocytes in the CNS and Schwann cells in the peripheral nervous system (PNS). Thus whether PGE 2 also plays a similar role in the myelination of CNS and PNS cell types requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Phospholipase A₂-activating protein is associated with a novel form of leukoencephalopathy

Zaccai

Savitzki

Zivony-Elboum

et al. 2016

Brain

View full text Add to dashboard Cite

*These authors contributed equally to this work.Leukoencephalopathies are a group of white matter disorders related to abnormal formation, maintenance, and turnover of myelin in the central nervous system. These disorders of the brain are categorized according to neuroradiological and pathophysiological criteria. Herein, we have identified a unique form of leukoencephalopathy in seven patients presenting at ages 2 to 4 months with progressive microcephaly, spastic quadriparesis, and global developmental delay. Clinical, metabolic, and imaging characterization of seven patients followed by homozygosity mapping and linkage analysis were performed. Next generation sequencing, bioinformatics, and segregation analyses followed, to determine a loss of function sequence variation in the phospholipase A 2 -activating protein encoding gene (PLAA). Expression and functional studies of the encoded protein were performed and included measurement of prostaglandin E 2 and cytosolic phospholipase A 2 activity in membrane fractions of fibroblasts derived from patients and healthy controls. Plaa-null mice were generated and prostaglandin E 2 levels were measured in different tissues. The novel phenotype of our patients segregated with a homozygous loss-of-function sequence variant, causing the substitution of leucine at position 752 to phenylalanine, in PLAA, which causes disruption of the protein's ability to induce prostaglandin E 2 and cytosolic phospholipase A 2 synthesis in patients' fibroblasts. Plaa-null mice were perinatal lethal with reduced brain levels of prostaglandin E 2 . The non-functional phospholipase A 2 -activating protein and the associated neurological phenotype, reported herein for the first time, join other complex phospholipid defects that cause leukoencephalopathies in humans, emphasizing the importance of this axis in white matter development and maintenance.

show abstract

Section: Discussionmentioning

confidence: 99%

Phospholipase A₂-activating protein is associated with a novel form of leukoencephalopathy

Zaccai

Savitzki

Zivony-Elboum

et al. 2016

Brain

View full text Add to dashboard Cite

show abstract

“…One of the best known axonal molecules essential for Schwann cell development is Neuregulin 1 (NRG1) type III [34,35]. Axonal NRG1 type III is cleaved extracellularly, and in the PNS, one consequence of this cleavage event is induction of prostaglandin D2 synthase (PGDS), which then catalyzes production of the hormone prostaglandin D2 (PGD2) [36]. PGD2 is a known ligand for the GPCR Gpr44, previously reported to be involved in cell-cell interactions during inflammatory responses [37,38].…”

Section: Gpcrs In Schwann Cells That Relay Signals From Axonsmentioning

confidence: 99%

“…Recently, this PGD2-Gpr44 signaling axis was demonstrated to play a key role in Schwann cell development: neuronal L-PGDS is secreted, which catalyzes the production of PGD2. PGD2 then binds to Gpr44 on Schwann cells, and Gpr44 activation dephosphorylates the transcription factor NFATc4 [36]. Dephosphorylation of NFATc4 allows for nuclear translocation and transcription of genes that promote Schwann cell differentiation [39].…”

Section: Gpcrs In Schwann Cells That Relay Signals From Axonsmentioning

confidence: 99%

See 1 more Smart Citation

G Protein-Coupled Receptors in Myelinating Glia

Mogha¹,

D’Rozario²,

Monk

2017

Trends in Pharmacological Sciences

View full text Add to dashboard Cite

The G protein-coupled receptor (GPCR) super-family represents the largest class of functionally selective drug targets for disease modulation and therapy. GPCRs have been studied in great detail in central nervous system (CNS) neurons, yet these important molecules have been relatively understudied in glia. In recent years, however, exciting new roles for GPCRs in glial cell biology have emerged. Here, we focus on key roles for GPCRs in a specialized subset of glia, myelinating glia. We highlight recent work firmly establishing GPCRs as regulators of myelinating glial cell development and myelin repair. These advancements expand our understanding of myelinating glial cell biology and underscore the utility of targeting GPCRs to promote myelin repair in human disease. KeywordsG protein-coupled receptor (GPCR); myelination; Schwann cell; oligodendrocyte; remyelination An overview of G protein-coupled receptors in the nervous systemThe G protein-coupled receptor (GPCR) super-family of seven transmembrane (7TM) receptors comprises the largest class of cell membrane receptors [1]. GPCRs are activated by myriad stimuli including peptides, hormones, light, proteolytic processing of their Ntermini, small molecules, and more traditional protein ligands [2,3]. GPCRs have emerged as major pharmacological drug targets due to their key roles in a variety of physiological functions in disease and health, and GPCR modulators represent at least one-third of all clinically marketed drugs [4]. GPCRs can be classified into five families using the phylogenetically based GRAFS system: glutamate, rhodopsin, adhesion, frizzled, and secretin [5]. Glutamate is a major excitatory neurotransmitter in the nervous system, and * Correspondence: monkk@wustl.edu (K.R. Monk). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Conflict of interest statementThe authors declare no competing conflicts. HHS Public Access Author ManuscriptAuthor Manuscript Author ManuscriptAuthor Manuscript accordingly, glutamate receptors have been studied in great detail with regard to their key roles in synaptic transmission, synapse formation, axon guidance, and development of neuronal circuits [6,7]. The rhodopsin family has by far the greatest number of GPCRs, and members are involved in photoreception and neurotransmission [5]. Frizzled GPCRs are activated by wingless/int (Wnt) proteins and control numerous cellular processes including neural crest development, patterning and adult neurogenesis [8]. Secretin receptors are classic hormone receptors, some of which have neuroprotective functions in the central nervou...

show abstract

“…Taken together, OPC can thus be seen as an additional cellular source of PTGDS expression in the CNS and OPC contribute to the neuromodulatory functions of PTGDS in an NG2-dependent manner. In the PNS, PTGDS is reported to be expressed by DRG neurons where the neuregulin I ICD influences expression levels (Trimarco et al, 2014).…”

Section: Intracellular Functions Of the Ng2 Proteoglycanmentioning

confidence: 99%

The role of the NG2 proteoglycan in OPC and CNS network function

Sakry

Trotter

2016

Brain Research

View full text Add to dashboard Cite

In the normal mammalian CNS, the NG2 proteoglycan is expressed by oligodendrocyte precursor cells (OPC) but not by any other neural cell-type. NG2 is a type-1 membrane protein, exerting multiple roles in the CNS including intracellular signaling within the OPC, with effects on migration, cytoskeleton interaction and target gene regulation. It has been recently shown that the extracellular region of NG2, in addition to an adhesive function, acts as a soluble ECM component with the capacity to alter defined neuronal network properties. This region of NG2 is thus endowed with neuromodulatory properties. In order to generate biologically active fragments yielding these properties, the sequential cleavage of the NG2 protein by α- and γ-secretases occurs. The basal level of constitutive cleavage is stimulated by neuronal network activity. This processing leads to 4 major NG2 fragments which all have been associated with distinct biological functions. Here we summarize these functions, focusing on recent discoveries and their implications for the CNS. This article is part of a Special Issue entitled SI:NG2-glia(Invited only).

show abstract

Prostaglandin D2 synthase/GPR44: a signaling axis in PNS myelination

Cited by 70 publications

References 59 publications

Phospholipase A₂-activating protein is associated with a novel form of leukoencephalopathy

Phospholipase A₂-activating protein is associated with a novel form of leukoencephalopathy

G Protein-Coupled Receptors in Myelinating Glia

The role of the NG2 proteoglycan in OPC and CNS network function

Contact Info

Product

Resources

About

Prostaglandin D2 synthase/GPR44: a signaling axis in PNS myelination

Cited by 70 publications

References 59 publications

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy

Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy

G Protein-Coupled Receptors in Myelinating Glia

The role of the NG2 proteoglycan in OPC and CNS network function

Contact Info

Product

Resources

About

Phospholipase A₂-activating protein is associated with a novel form of leukoencephalopathy

Phospholipase A₂-activating protein is associated with a novel form of leukoencephalopathy