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GPR56/ADGRG1 regulates development and maintenance of peripheral myelin


Ackerman, Sarah D; Luo, Rong; Poitelon, Yannick; Mogha, Amit; Harty, Breanne L; D’Rozario, Mitchell; Sanchez, Nicholas E; Lakkaraju, Asvin K K; Gamble, Paul; Li, Jun; Qu, Jun; MacEwan, Matthew R; Ray, Wilson Zachary; Aguzzi, Adriano; Feltri, M Laura; Piao, Xianhua; Monk, Kelly R (2018). GPR56/ADGRG1 regulates development and maintenance of peripheral myelin. Journal of Experimental Medicine, 215(3):941-961.

Abstract

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/ADGRG1 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.

Abstract

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/ADGRG1 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:5 March 2018
Deposited On:19 Mar 2018 19:34
Last Modified:18 Apr 2018 11:49
Publisher:Rockefeller University Press
ISSN:0022-1007
Funders:SNF, ERC, SystemsX.ch, Synapsis Foundation, CRPP
OA Status:Green
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1084/jem.20161714
PubMed ID:29367382
Project Information:
  • : FunderH2020
  • : Grant ID670958
  • : Project TitlePRION2020 - Function and malfunction of the prion protein
  • : FunderSNSF
  • : Grant ID
  • : Project TitleSNF
  • : Funder
  • : Grant ID
  • : Project TitleERC
  • : Funder
  • : Grant ID
  • : Project TitleSystemsX.ch
  • : Funder
  • : Grant ID
  • : Project TitleSynapsis Foundation
  • : Funder
  • : Grant ID
  • : Project TitleCRPP

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