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Science 325 (5946): 1402-1405

Copyright © 2009 by the American Association for the Advancement of Science

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

Kelly R. Monk,1 Stephen G. Naylor,1 Thomas D. Glenn,1 Sara Mercurio,1 Julie R. Perlin,1 Claudia Dominguez,1 Cecilia B. Moens,2 William S. Talbot1

Abstract: The myelin sheath allows axons to conduct action potentials rapidly in the vertebrate nervous system. Axonal signals activate expression of specific transcription factors, including Oct6 and Krox20, that initiate myelination in Schwann cells. Elevation of cyclic adenosine monophosphate (cAMP) can mimic axonal contact in vitro, but the mechanisms that regulate cAMP levels in vivo are unknown. Using mutational analysis in zebrafish, we found that the G protein–coupled receptor 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.

1 Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
2 Howard Hughes Medical Institute and Division of Basic Science, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

* To whom correspondence should be addressed. E-mail: william.talbot{at}

Haplotype-specific modulation of a SOX10/CREB response element at the Charcot-Marie-Tooth disease type 4C locus SH3TC2.
M. H. Brewer, K. H. Ma, G. W. Beecham, C. Gopinath, the Inherited Neuropathy Consortium (INC), F. Baas, B.-O. Choi, M. M. Reilly, M. E. Shy, S. Zuchner, et al. (2014)
Hum. Mol. Genet.
   Abstract »    Full Text »    PDF »
Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects.
A. Laquerriere, J. Maluenda, A. Camus, L. Fontenas, K. Dieterich, F. Nolent, J. Zhou, N. Monnier, P. Latour, D. Gentil, et al. (2014)
Hum. Mol. Genet. 23, 2279-2289
   Abstract »    Full Text »    PDF »
Dissection of a Krox20 positive feedback loop driving cell fate choices in hindbrain patterning.
Y. X. Bouchoucha, J. Reingruber, C. Labalette, M. A. Wassef, E. Thierion, C. Desmarquet-Trin Dinh, D. Holcman, P. Gilardi-Hebenstreit, and P. Charnay (2014)
Mol Syst Biol 9, 690
   Abstract »    Full Text »    PDF »
Transcriptional Regulation Induced by cAMP Elevation in Mouse Schwann Cells.
D. Schmid, T. Zeis, and N. Schaeren-Wiemers (2014)
ASN Neuro 6, AN20130031
   Abstract »    Full Text »    PDF »
Hoxb1b controls oriented cell division, cell shape and microtubule dynamics in neural tube morphogenesis.
M. Zigman, N. Laumann-Lipp, T. Titus, J. Postlethwait, and C. B. Moens (2014)
Development 141, 639-649
   Abstract »    Full Text »    PDF »
The Protein Kinase A Regulatory Subunit R1A (Prkar1a) Plays Critical Roles in Peripheral Nerve Development.
L. Guo, A. A. Lee, T. A. Rizvi, N. Ratner, and L. S. Kirschner (2013)
J. Neurosci. 33, 17967-17975
   Abstract »    Full Text »    PDF »
Gpr126 Functions in Schwann Cells to Control Differentiation and Myelination via G-Protein Activation.
A. Mogha, A. E. Benesh, C. Patra, F. B. Engel, T. Schoneberg, I. Liebscher, and K. R. Monk (2013)
J. Neurosci. 33, 17976-17985
   Abstract »    Full Text »    PDF »
Semicircular canal morphogenesis in the zebrafish inner ear requires the function of gpr126 (lauscher), an adhesion class G protein-coupled receptor gene.
F.-S. Geng, L. Abbas, S. Baxendale, C. J. Holdsworth, A. G. Swanson, K. Slanchev, M. Hammerschmidt, J. Topczewski, and T. T. Whitfield (2013)
Development 140, 4362-4374
   Abstract »    Full Text »    PDF »
Organ-specific function of adhesion G protein-coupled receptor GPR126 is domain-dependent.
C. Patra, M. J. van Amerongen, S. Ghosh, F. Ricciardi, A. Sajjad, T. Novoyatleva, A. Mogha, K. R. Monk, C. Muhlfeld, and F. B. Engel (2013)
PNAS 110, 16898-16903
   Abstract »    Full Text »    PDF »
notch3 is essential for oligodendrocyte development and vascular integrity in zebrafish.
A. Zaucker, S. Mercurio, N. Sternheim, W. S. Talbot, and F. L. Marlow (2013)
Dis. Model. Mech. 6, 1246-1259
   Abstract »    Full Text »    PDF »
Analysis of Gpr126 function defines distinct mechanisms controlling the initiation and maturation of myelin.
T. D. Glenn and W. S. Talbot (2013)
Development 140, 3167-3175
   Abstract »    Full Text »    PDF »
Gpr125 modulates Dishevelled distribution and planar cell polarity signaling.
X. Li, I. Roszko, D. S. Sepich, M. Ni, H. E. Hamm, F. L. Marlow, and L. Solnica-Krezel (2013)
Development 140, 3028-3039
   Abstract »    Full Text »    PDF »
Mice overexpressing CD97 in intestinal epithelial cells provide a unique model for mammalian postnatal intestinal cylindrical growth.
G. Aust, C. Kerner, S. Gonsior, D. Sittig, H. Schneider, P. Buske, M. Scholz, N. Dietrich, S. Oldenburg, O. N. Karpus, et al. (2013)
Mol. Biol. Cell 24, 2256-2268
   Abstract »    Full Text »    PDF »
Sticky Signaling--Adhesion Class G Protein-Coupled Receptors Take the Stage.
T. Langenhan, G. Aust, and J. Hamann (2013)
Science Signaling 6, re3
   Abstract »    Full Text »    PDF »
The Adhesion-GPCR BAI1 Regulates Synaptogenesis by Controlling the Recruitment of the Par3/Tiam1 Polarity Complex to Synaptic Sites.
J. G. Duman, C. P. Tzeng, Y.-K. Tu, T. Munjal, B. Schwechter, T. S.-Y. Ho, and K. F. Tolias (2013)
J. Neurosci. 33, 6964-6978
   Abstract »    Full Text »    PDF »
RNA-seq-based mapping and candidate identification of mutations from forward genetic screens.
A. C. Miller, N. D. Obholzer, A. N. Shah, S. G. Megason, and C. B. Moens (2013)
Genome Res. 23, 679-686
   Abstract »    Full Text »    PDF »
Loss of SOX10 function contributes to the phenotype of human Merlin-null schwannoma cells.
R. D. S. Doddrell, X.-P. Dun, A. Shivane, M. L. Feltri, L. Wrabetz, M. Wegner, E. Sock, C. O. Hanemann, and D. B. Parkinson (2013)
Brain 136, 549-563
   Abstract »    Full Text »    PDF »
Mutation of sec63 in zebrafish causes defects in myelinated axons and liver pathology.
K. R. Monk, M. G. Voas, C. Franzini-Armstrong, I. S. Hakkinen, and W. S. Talbot (2013)
Dis. Model. Mech. 6, 135-145
   Abstract »    Full Text »    PDF »
Rac1 Controls Schwann Cell Myelination through cAMP and NF2/merlin.
L. Guo, C. Moon, K. Niehaus, Y. Zheng, and N. Ratner (2012)
J. Neurosci. 32, 17251-17261
   Abstract »    Full Text »    PDF »
Adhesion G Protein-Coupled Receptors: Signaling, Pharmacology, and Mechanisms of Activation.
K. J. Paavola and R. A. Hall (2012)
Mol. Pharmacol. 82, 777-783
   Abstract »    Full Text »    PDF »
Activation of Myeloid Cell-Specific Adhesion Class G Protein-Coupled Receptor EMR2 via Ligation-Induced Translocation and Interaction of Receptor Subunits in Lipid Raft Microdomains.
Y.-S. Huang, N.-Y. Chiang, C.-H. Hu, C.-C. Hsiao, K.-F. Cheng, W.-P. Tsai, S. Yona, M. Stacey, S. Gordon, G.-W. Chang, et al. (2012)
Mol. Cell. Biol. 32, 1408-1420
   Abstract »    Full Text »    PDF »
A novel evolutionarily conserved domain of cell-adhesion GPCRs mediates autoproteolysis.
D. Arac, A. A. Boucard, M. F. Bolliger, J. Nguyen, S. M. Soltis, T. C. Sudhof, and A. T. Brunger (2012)
EMBO J. 31, 1364-1378
   Abstract »    Full Text »    PDF »
Cell Adhesion Receptor GPR133 Couples to Gs Protein.
J. Bohnekamp and T. Schoneberg (2011)
J. Biol. Chem. 286, 41912-41916
   Abstract »    Full Text »    PDF »
MLCK regulates Schwann cell cytoskeletal organization, differentiation and myelination.
E. M. Leitman, A. Tewari, M. Horn, M. Urbanski, E. Damanakis, S. Einheber, J. L. Salzer, P. de Lanerolle, and C. V. Melendez-Vasquez (2011)
J. Cell Sci. 124, 3784-3796
   Abstract »    Full Text »    PDF »
Neuronal Neuregulin 1 type III directs Schwann cell migration.
J. R. Perlin, M. E. Lush, W. Z. Stephens, T. Piotrowski, and W. S. Talbot (2011)
Development 138, 4639-4648
   Abstract »    Full Text »    PDF »
Individual axons regulate the myelinating potential of single oligodendrocytes in vivo.
R. G. Almeida, T. Czopka, C. ffrench-Constant, and D. A. Lyons (2011)
Development 138, 4443-4450
   Abstract »    Full Text »    PDF »
GPR56 Regulates VEGF Production and Angiogenesis during Melanoma Progression.
L. Yang, G. Chen, S. Mohanty, G. Scott, F. Fazal, A. Rahman, S. Begum, R. O. Hynes, and L. Xu (2011)
Cancer Res. 71, 5558-5568
   Abstract »    Full Text »    PDF »
Gpr126 is essential for peripheral nerve development and myelination in mammals.
K. R. Monk, K. Oshima, S. Jors, S. Heller, and W. S. Talbot (2011)
Development 138, 2673-2680
   Abstract »    Full Text »    PDF »
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N. B. Jagalur, M. Ghazvini, W. Mandemakers, S. Driegen, A. Maas, E. A. Jones, M. Jaegle, F. Grosveld, J. Svaren, and D. Meijer (2011)
J. Neurosci. 31, 8585-8594
   Abstract »    Full Text »    PDF »
The cell-adhesion G protein-coupled receptor BAI3 is a high-affinity receptor for C1q-like proteins.
M. F. Bolliger, D. C. Martinelli, and T. C. Sudhof (2011)
PNAS 108, 2534-2539
   Abstract »    Full Text »    PDF »
Hindbrain patterning requires fine-tuning of early krox20 transcription by Sprouty 4.
C. Labalette, Y. X. Bouchoucha, M. A. Wassef, P. A. Gongal, J. Le Men, T. Becker, P. Gilardi-Hebenstreit, and P. Charnay (2011)
Development 138, 317-326
   Abstract »    Full Text »    PDF »
Regulation of Oligodendrocyte Differentiation and Myelination.
B. Emery (2010)
Science 330, 779-782
   Abstract »    Full Text »    PDF »
Schwann Cell Dedifferentiation Is Independent of Mitogenic Signaling and Uncoupled to Proliferation: ROLE OF cAMP AND JNK IN THE MAINTENANCE OF THE DIFFERENTIATED STATE.
P. V. Monje, J. Soto, K. Bacallao, and P. M. Wood (2010)
J. Biol. Chem. 285, 31024-31036
   Abstract »    Full Text »    PDF »
A G-coupled Receptor Protein Critical for Peripheral Nerve Myelination.
S. Y. B. Howng, D. S. Douglas, and B. Popko (2010)
J Mol Cell Biol 2, 105-106
   Abstract »    Full Text »    PDF »
Adam22 Is a Major Neuronal Receptor for Lgi4-Mediated Schwann Cell Signaling.
E. Ozkaynak, G. Abello, M. Jaegle, L. van Berge, D. Hamer, L. Kegel, S. Driegen, K. Sagane, J. R. Bermingham Jr, and D. Meijer (2010)
J. Neurosci. 30, 3857-3864
   Abstract »    Full Text »    PDF »
Schwann Cells Inhibit Ectopic Clustering of Axonal Sodium Channels.
M. G. Voas, T. D. Glenn, A. R. Raphael, and W. S. Talbot (2009)
J. Neurosci. 29, 14408-14414
   Abstract »    Full Text »    PDF »
Went Fishing, Caught a Snake.
D. Meijer (2009)
Science 325, 1353-1354
   Abstract »    Full Text »    PDF »

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