The adhesion GPCR Gpr56 regulates oligodendrocyte development via interactions with Gα12/13 and RhoA.

Sarah D Ackerman,David H Gutmann,Cynthia Garcia,Xianhua Piao,Kelly R Monk

doi:10.1038/ncomms7122

Abstract

In the vertebrate central nervous system, myelinating oligodendrocytes are postmitotic and derive from proliferative oligodendrocyte precursor cells (OPCs). The molecular mechanisms that govern oligodendrocyte development are incompletely understood, but recent studies implicate the adhesion class of G protein-coupled receptors (aGPCRs) as important regulators of myelination. Here, we use zebrafish and mouse models to dissect the function of the aGPCR Gpr56 in oligodendrocyte development. We show that gpr56 is expressed during early stages of oligodendrocyte development. Additionally, we observe a significant reduction of mature oligodendrocyte number and of myelinated axons in gpr56 zebrafish mutants. This reduction results from decreased OPC proliferation, rather than increased cell death or altered neural precursor differentiation potential. Finally, we show that these functions are mediated by Gα12/13 proteins and Rho activation. Together, our data establish Gpr56 as a regulator of oligodendrocyte development.

Highlights

In the vertebrate central nervous system, myelinating oligodendrocytes are postmitotic and derive from proliferative oligodendrocyte precursor cells (OPCs)
In addition to the canonical seven-transmembrane (7TM) domain common to all GPCRs that usually facilitates intracellular signalling, adhesion class of G protein-coupled receptors (aGPCRs) are characterized by the presence of a very large N-terminal domain rich in functional motifs associated with cell–cell and cell–matrix adhesion, which is separated from the 7-Transmembrane Domain (7TM) by a GPCR proteolytic site (GPS)[14]
Published data sets indicate that Gpr[56], an aGPCR related to Gpr[126], is highly expressed during mouse central nervous system (CNS) development in oligodendrocyte precursor cells (OPCs)[17,18]

Summary

Introduction

In the vertebrate central nervous system, myelinating oligodendrocytes are postmitotic and derive from proliferative oligodendrocyte precursor cells (OPCs). We observe a significant reduction of mature oligodendrocyte number and myelinated axons in gpr[56] zebrafish mutants This reduction results from decreased OPC proliferation, rather than increased cell death or altered neural precursor differentiation potential. Previous studies indicate that extracellular matrix proteins and their receptors, in addition to intracellular signal-transduction cascades, are essential for proper development of myelinating glial cells[6,7]. The dual roles of aGPCRs in promoting cell–cell/cell–matrix interactions and facilitating intracellular signalling, in addition to the importance of Gpr[126] for SC myelination[10–13], led us to hypothesize that additional aGPCRs regulate glial cell development and myelination in the CNS. Brains of BFPP patients exhibit reduced white matter volume by MRI20–22, indicative of myelin defects Taken together, these data suggest that Gpr[56] may function in oligodendrocyte development. Transient overexpression of gpr[56] in wild-type (WT)

Methods

Findings

Conclusion