title: The adhesion GPCR GPR126 has distinct, domain-dependent functions in Schwann cell development mediated by interaction with laminin-211.
abstract: Myelin ensheathes axons to allow rapid propagation of action potentials and proper nervous system function. In the peripheral nervous system, Schwann cells (SCs) radially sort axons into a 1:1 relationship before wrapping an axonal segment to form myelin. SC myelination requires the adhesion G protein-coupled receptor GPR126, which undergoes autoproteolytic cleavage into an N-terminal fragment (NTF) and a seven-transmembrane-containing C-terminal fragment (CTF). Here we show that GPR126 has domain-specific functions in SC development whereby the NTF is necessary and sufficient for axon sorting, whereas the CTF promotes wrapping through cAMP elevation. These biphasic roles of GPR126 are governed by interactions with Laminin-211, which we define as a novel ligand for GPR126 that modulates receptor signaling via a tethered agonist. Our work suggests a model in which Laminin-211 mediates GPR126-induced cAMP levels to control early and late stages of SC development.
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Petersen
authors.affiliation: Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Luo
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Ines
authors.initials: I
authors.lastname: Liebscher
authors.affiliation: Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Giera
authors.affiliation: Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sung-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Mogha
authors.affiliation: Department of Biochemistry, University of Buffalo, The State University of New York, Buffalo, NY 14023, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Ghidinelli
authors.affiliation: Department of Biochemistry, University of Buffalo, The State University of New York, Buffalo, NY 14023, USA.
authors.forename: M Laura
authors.initials: ML
authors.lastname: Feltri
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Schöneberg
authors.affiliation: Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: xianhua.piao@childrens.harvard.edu.
authors.forename: Xianhua
authors.initials: X
authors.lastname: Piao
authors.affiliation: Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: monkk@wustl.edu.
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Monk
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D066298:In Vitro Techniques; D007797:Laminin / Q000235:genetics / Q000378:metabolism*; D007814:Larva; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D060172:Morpholinos / Q000494:pharmacology; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D009457:Neuroglia / Q000378:metabolism / Q000648:ultrastructure; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012583:Schwann Cells / Q000378:metabolism* / Q000648:ultrastructure; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C550767:Gpr126 protein, mouse; D007797:Laminin; D060172:Morpholinos; D043562:Receptors, G-Protein-Coupled; D029961:Zebrafish Proteins; C102645:laminin alpha 2