A G Protein–Coupled Receptor Is Essential for Schwann Cells to Initiate Myelination

Abstract

The myelin sheath allows axons to rapidly conduct action potentials in the vertebrate nervous system. Incompletely understood axonal signals activate specific transcription factors, including Oct6 and Krox20, that initiate myelination in Schwann cells. Elevation of cAMP can mimic axonal contact in vitro, but the mechanisms that regulate cAMP levels in vivo are unknown. Using mutational analysis in zebrafish, we report that Gpr126 is required autonomously in Schwann cells for myelination. In gpr126 mutants, Schwann cells failed to express oct6 and krox20, and were arrested at the promyelinating stage. Elevation of cAMP in gpr126 mutants, but not krox20 mutants, could restore myelination. We propose that Gpr126 drives the differentiation of promyelinating Schwann cells by elevating cAMP levels, thereby triggering Oct6 expression and myelination.During peripheral nervous system (PNS) development, promyelinating Schwann cells associate with one segment of an axon and differentiate into myelinating Schwann cells that iteratively wrap their membrane around an axonal segment to form the myelin sheath (1). Axonal signals transiently activate the expression of the transcription factor Oct6 in Schwann cells that will form myelin, and cAMP can mimic axonal contact in vitro (2,3). Oct6 regulates Krox20 expression (4), and both transcription factors are required for Schwann cells to initiate myelination (5-7). Neuregulin signals and their ErbB receptors are involved in regulation of Oct6 and Krox20 (8), but the signaling pathways in Schwann cells that regulate myelination are not well understood.In a genetic screen for zebrafish mutants with abnormalities in myelinated axons, we previously identified two allelic mutations, st49 and st63, in which Myelin basic protein (Mbp) expression was not observed in peripheral nerves (9). Central nervous system (CNS) Mbp expression and PNS axonal marker expression were unaffected (9; Fig. S1). Except for an enlargement of the ear that was evident at 5 days post fertilization (dpf), st49 homozygous mutant larvae were morphologically indistinguishable from wild-type and heterozygous siblings (Fig. S2). High-resolution mapping experiments placed the st49 mutation in a region of Linkage Group 20 (LG20) that contains g-protein coupled receptor 126 (gpr126), which encodes a member of the adhesion G-protein coupled receptor (GPCR)

Neuregulin/ErbB Signaling in Developmental Myelin Formation and Nerve Repair

“…Myelination in GPR126 mutant fish is rescued by forskolin in the swimming water (Monk et al, 2009). GPR126 is activated by binding to laminin and collagen, providing evidence that the extracellular matrix formed by immature Schwann cells provides signals that control entry into myelination (Paavola et al, 2014;Petersen et al, 2015).…”

“…In vivo, cAMP-mediated signals provided by the G protein-coupled receptor GPR126 are essential for myelination, and mutations of GPR126 preclude peripheral myelination in zebrafish and mice (Monk et al, 2009;Monk et al, 2011).…”

The Role of Neuregulin-1 In the Response To Nerve Injury

“…This is also an illustration of cooperation between NRG1 and another axon-derived pro-myelin signal. An as-yet unidentified axonal ligand activates GPR 126, which is expressed on SCs, leading to increased cAMP, which is critical for myelination [68]. NRG1-induced expression of Krox 20 and myelin-related proteins in mouse SCs requires the presence of elevated cAMP [62].…”

Characterization and functional study of a cluster of four highly conserved orphan adhesion‐GPCR in mouse

“…This initiative has revealed that Gpr126, a vertebrate aGPCR essential for the myelination of peripheral nerves by Schwann cells (Monk et al, 2009(Monk et al, , 2011, is required for embryonic viability and cardiovascular development in the mouse (Waller-Evans et al, 2010).…”