Gpr126 functions in Schwann cells to control differentiation and myelination via G-protein activation.
The myelin sheath surrounding axons ensures that nerve impulses travel quickly and efficiently, allowing for the proper function of the vertebrate nervous system. We previously showed that the adhesion G-protein-coupled receptor (aGPCR) Gpr126 is essential for peripheral nervous system myelination, although the molecular mechanisms by which Gpr126 functions were incompletely understood. aGPCRs are a significantly understudied protein class, and it was unknown whether Gpr126 couples to G-proteins. Here, we analyze Dhh(Cre);Gpr126(fl/fl) conditional mutants, and show that Gpr126 functions in Schwann cells (SCs) for radial sorting of axons and myelination. Furthermore, we demonstrate that elevation of cAMP levels or protein kinase A activation suppresses myelin defects in Gpr126 mouse mutants and that cAMP levels are reduced in conditional Gpr126 mutant peripheral nerve. Finally, we show that GPR126 directly increases cAMP by coupling to heterotrimeric G-proteins. Together, these data support a model in which Gpr126 functions in SCs for proper development and myelination and provide evidence that these functions are mediated via G-protein-signaling pathways.
Department of Developmental Biology, Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110 Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany, Experimental Renal and Cardiovascular Research, Department of Nephropathology, Institute of Pathology, University of Erlangen-Nürnberg, 91054 Erlangen, Germany, and Institute of Biochemistry, Molecular Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.
Amit
A
Mogha
Andrew E
AE
Benesh
Chinmoy
C
Patra
Felix B
FB
Engel
Torsten
T
Schöneberg
Ines
I
Liebscher
Kelly R
KR
Monk
D000818:Animals; D019556:COS Cells; D002454:Cell Differentiation / Q000502:physiology*; D002522:Chlorocebus aethiops; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D012583:Schwann Cells / Q000378:metabolism* / Q000648:ultrastructure; D015398:Signal Transduction / Q000502:physiology
C488660:ADGRG6 protein, human; D043562:Receptors, G-Protein-Coupled; D019204:GTP-Binding Proteins