TY - JOUR
T1 - GPR56/ADG RG1 regulates development and maintenance of peripheral myelin
AU - Ackerman, Sarah D.
AU - Luo, Rong
AU - Poitelon, Yannick
AU - Mogha, Amit
AU - Harty, Breanne L.
AU - D'Rozario, Mitchell
AU - Sanchez, Nicholas E.
AU - Lakkaraju, Asvin K.K.
AU - Gamble, Paul
AU - Li, Jun
AU - Qu, Jun
AU - MacEwan, Matthew R.
AU - Ray, Wilson Zachary
AU - Aguzzi, Adriano
AU - Feltri, M. Laura
AU - Piao, Xianhua
AU - Monk, Kelly R.
N1 - Funding Information:
We thank members of the Monk laboratory for helpful discussions. We thank Fang Lin for 3MOs, Lila Solnica-Krezel for the rhov14 construct, Jeffrey Milbrandt for cDNAs, and Robyn Roth for assistance with TEM. We thank Charleen Johnson and Zachary Spence for husbandry assistance, Bo Zhang for statistical consultations, and Marcus Mahar for his aid in RNA-seq analysis. Finally, we thank Gerhard Wiche for sharing his expertise on plectin biology. This work was supported by a predoctoral fellowship from the National Institutes of Health to S.D. Ackerman (F31 NS087801), to B.L. Harty (F31 NS094004), to M. D’Rozario (F32 NS100461), to M.L. Feltri (R01NS045630), and to W.Z. Ray (K23 NS084932); by a research grant from the Muscular Dystrophy Association to X. Piao and K.R. Monk (293295); and by grants to K.R. Monk from the National Institutes of Health (R01 NS079445) and the Edward J. Mallinckrodt, Jr. Foundation. A. Aguzzi is the recipient of an Advanced Grant of the European Research Council, a European Union Seventh Framework Programme grant (NEURINOX), the Swiss National Science Foundation, the Clinical Research Priority Programs Small RNAs and Human Hemato-Lymphatic Diseases, SystemsX.ch (PrionX and SynucleiX), and the Novartis Foundation. A.K.K. Lakkaraju was supported by a grant from the Synapsis Foundation. The authors declare no competing financial interests.
Publisher Copyright:
© 2018 Ackerman et al.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - Myelin is a multilamellar sheath generated by specialized glia called Schwann cells (SCs) in the peripheral nervous system (PNS), which serves to protect and insulate axons for rapid neuronal signaling. In zebrafish and rodent models, we identify GPR56/ADG RG1 as a conserved regulator of PNS development and health. We demonstrate that, during SC development, GPR56-dependent RhoA signaling promotes timely radial sorting of axons. In the mature PNS, GPR56 is localized to distinct SC cytoplasmic domains, is required to establish proper myelin thickness, and facilitates organization of the myelin sheath. Furthermore, we define plectin-a scaffolding protein previously linked to SC domain organization, myelin maintenance, and a series of disorders termed "plectinopathies"-as a novel interacting partner of GPR56. Finally, we show that Gpr56 mutants develop progressive neuropathy-like symptoms, suggesting an underlying mechanism for peripheral defects in some human patients with GPR56 mutations. In sum, we define Gpr56 as a new regulator in the development and maintenance of peripheral myelin.
AB - Myelin is a multilamellar sheath generated by specialized glia called Schwann cells (SCs) in the peripheral nervous system (PNS), which serves to protect and insulate axons for rapid neuronal signaling. In zebrafish and rodent models, we identify GPR56/ADG RG1 as a conserved regulator of PNS development and health. We demonstrate that, during SC development, GPR56-dependent RhoA signaling promotes timely radial sorting of axons. In the mature PNS, GPR56 is localized to distinct SC cytoplasmic domains, is required to establish proper myelin thickness, and facilitates organization of the myelin sheath. Furthermore, we define plectin-a scaffolding protein previously linked to SC domain organization, myelin maintenance, and a series of disorders termed "plectinopathies"-as a novel interacting partner of GPR56. Finally, we show that Gpr56 mutants develop progressive neuropathy-like symptoms, suggesting an underlying mechanism for peripheral defects in some human patients with GPR56 mutations. In sum, we define Gpr56 as a new regulator in the development and maintenance of peripheral myelin.
UR - http://www.scopus.com/inward/record.url?scp=85042865812&partnerID=8YFLogxK
U2 - 10.1084/jem.20161714
DO - 10.1084/jem.20161714
M3 - Article
C2 - 29367382
AN - SCOPUS:85042865812
SN - 0022-1007
VL - 215
SP - 941
EP - 961
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 3
ER -