The oligodendrocyte-enriched orphan G protein-coupled receptor Gpr62 is dispensable for central nervous system myelination

Curtis M Hay,Matthias Koenning,Trevor J Kilpatrick,Helena Bujalka,Daniel J Scott,Aesoon L Bensen,Ben Emery,Stacey Jackson,Stanislaw Mitew

doi:10.1186/s13064-021-00156-y

Abstract

BackgroundMyelination is a highly regulated process in the vertebrate central nervous system (CNS) whereby oligodendrocytes wrap axons with multiple layers of insulating myelin in order to allow rapid electrical conduction. Establishing the proper pattern of myelin in neural circuits requires communicative axo-glial interactions, however, the molecular interactions that occur between oligodendrocytes and axons during developmental myelination and myelin maintenance remain to be fully elucidated. Our previous work identified G protein-coupled receptor 62 (Gpr62), an uncharacterized orphan g-protein coupled receptor, as being selectively expressed by mature oligodendrocytes within the CNS, suggesting a potential role in myelination or axoglial interactions. However, no studies to date have assessed the functional requirement for Gpr62 in oligodendrocyte development or CNS myelination.MethodsTo address this, we generated a knockout mouse strain lacking the Gpr62 gene. We assessed CNS myelination during both postnatal development and adulthood using immunohistochemistry, electron microscopy and western blot. In addition, we utilized AAV-mediated expression of a tagged Gpr62 in oligodendrocytes to determine the subcellular localization of the protein in vivo.ResultsWe find that virally expressed Gpr62 protein is selectively expressed on the adaxonal myelin layer, suggestive of a potential role for Gpr62 in axo-myelinic signaling. Nevertheless, Gpr62 knockout mice display normal oligodendrocyte numbers and apparently normal myelination within the CNS during both postnatal development and adulthood.ConclusionsWe conclude that in spite of being well-placed to mediate neuronal-oligodendrocyte communications, Gpr62 is overall dispensable for CNS myelination.

Highlights

Myelination is a highly regulated process in the vertebrate central nervous system (CNS) whereby oligodendrocytes wrap axons with multiple layers of insulating myelin in order to allow rapid electrical conduction
We subsequently confirmed via in situ hybridization that the distribution of G protein-coupled receptor 62 (Gpr62) expressing cells in the brain matched the expected pattern for mature oligodendrocytes [24]. This high-enrichment of Gpr62 expression in myelinating oligodendrocytes has subsequently been confirmed by both bulk and single cell RNA-Seq experiments [35, 36], both of which identify strongest expression of Gpr62 in the mature oligodendrocyte populations (Fig. 1A, B) and little or no expression in Oligodendrocyte progenitor cell (OPC) or other CNS populations
This study sought to identify the role of the orphan G protein-coupled receptors (GPCRs) Gpr62 in CNS myelination

Summary

Introduction

Myelination is a highly regulated process in the vertebrate central nervous system (CNS) whereby oligodendrocytes wrap axons with multiple layers of insulating myelin in order to allow rapid electrical conduction. Hay et al Neural Development (2021) 16:6 properly transmit electrical signals and eventually degenerate, sometimes leading to significant and debilitating neurological deficits During both developmental and adult myelination, resident oligodendrocyte progenitor cells (OPCs) proliferate, differentiate into postmitotic oligodendrocytes, contact multiple nearby axons and commit to myelinating a subset of these axons [9]. Once established myelin becomes relatively stable, there is evidence that even mature myelin sheaths may be capable of some degree of remodelling [12,13,14,15] Fundamental to understanding both developmental myelination and myelin plasticity is elucidation of the signals that neurons and other CNS cell types provide to regulate OPC and oligodendrocyte behaviour. The adhesion GPCR Gpr prevents precocious OPC differentiation; mouse and fish mutants for Gpr show enhanced OPC differentiation and reduced proliferation at early ages, leading to a subsequent depletion of OPCs and myelinating cells at later stages of development [21,22,23]

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