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Review
. 2017 Apr;246(4):275-284.
doi: 10.1002/dvdy.24473. Epub 2017 Jan 11.

Adhesion G-protein Coupled Receptors and Extracellular Matrix Proteins: Roles in Myelination and Glial Cell Development

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Free PMC article
Review

Adhesion G-protein Coupled Receptors and Extracellular Matrix Proteins: Roles in Myelination and Glial Cell Development

Paulomi Mehta et al. Dev Dyn. .
Free PMC article

Abstract

Adhesion G protein-coupled receptors (aGPCRs) are a large family of transmembrane proteins that play important roles in many processes during development, primarily through cell-cell and cell-extracellular matrix (ECM) interactions. In the nervous system, they have been linked to the complex process of myelination, both in the central and peripheral nervous system. GPR126 is essential in Schwann cell-mediated myelination in the peripheral nervous system (PNS), while GPR56 is involved in oligodendrocyte development central nervous system (CNS) myelination. VLGR1 is another aGPCR that is associated with the expression of myelin-associated glycoprotein (MAG) which has inhibitory effects on the process of nerve repair. The ECM is composed of a vast array of structural proteins, three of which interact specifically with aGPCRs: collagen III/GPR56, collagen IV/GPR126, and laminin-211/GPR126. As druggable targets, aGPCRs are valuable in their ability to unlock treatment for a wide variety of currently debilitating myelin disorders. Developmental Dynamics 246:275-284, 2017. © 2016 Wiley Periodicals, Inc.

Keywords: development; injury response; signaling.

Figures

Figure 1
Figure 1
Cartoon depicting the general structure and signaling mechanism for aGPCRs. A) General structure of aGPCRs. Adhesion GPCRs are characterized by their extremely long N-terminal fragment (NTF) that contains a GAIN domain, within which is the site of autoproteolysis (GPS). The C-terminal fragment (CTF) contains a 7-transmembrane domain (7-TM). After autoproteolysis, the NTF and the CTF remain covalently associated at the cell surface. B) Tethered agonist activation. Upon ligand binding, the NTF detaches from the CTF and uncovers the tethered agonist peptide signal, which interacts with the 7-TM and facilitates downstream G-protein signaling.
Figure 2
Figure 2
GPR56 promotes OPC proliferation. A) As OPCs progress through differentiation, they begin to extend their processes and create complex branching structures, with the mature myelinating OLs wrapping their processes around axons to create a myelin sheath. GPR56 is highly expressed in glial progenitors and OPCs, but is downregulated in O4+ immature OLs, with little to no expression noted by mature OLs. B) GPR56 binds an unknown ligand that leads to downstream RhoA activation through coupling to Gα12/13. RhoA activation then leads to OPC proliferation. PLL, Pentraxin/Laminin/neurexin/sex-hormone-binding-globulin-like domain.
Figure 3
Figure 3
GPR126 regulates both radial sorting and myelination. A) Immature SCs migrate through the PNS, enveloping several axons before undergoing radial sorting and then proceeding down one of two distinct pathways. The first pathway involves the SC selecting and ensheathing a single axon (as a promyelinating SC) and then continuing on to myelinate that specific axon. The second involves becoming a non-myelinating SC that creates “Remak bundles” of non-myelinated axons. These Remak cells also play important roles in repair of myelin damage. The developmental expression of GPR126 is not known. However, current literature suggests that GPR126 is expressed in both immature and mature SCs. Loss of GPR126 leads to a breakdown in both pathways, with SCs arrested in the promyelinating phase, as well as decreased numbers of non-myelinating SCs. B) Collagen IV binds to GPR126 in the region of the CUB-PTX domains which leads to elevation of cAMP. C) In the beginning stages of development, laminin-211 exists as monomers and does not have sufficient interaction with GPR126 to stimulate downstream cAMP signaling. As the basal lamina matures, laminin-211 self-polymerizes and generates adequate force to facilitate GPR126 tethered agonist mediated signaling, increasing downstream cAMP and initiating myelin formation. D) The most recently discovered ligand of GPR126 is PrPc, a prion protein, that has an amino-terminal flexible tail that contains a cAMP inducing domain similar to that found on collagen IV. Application of this moiety was enough to induce a GPR126-dependent cAMP response. CUB, C1r/C1s domain; PTX, pentraxin domain.

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