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J Exp Med. 2018 Mar 5;215(3):941-961. doi: 10.1084/jem.20161714. Epub 2018 Jan 24.

GPR56/ADGRG1 regulates development and maintenance of peripheral myelin.

Author information

1
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO.
2
Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, MA.
3
Departments of Biochemistry and Neurology, Hunter James Kelly Research Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY.
4
Institute of Neuropathology, University of Zurich, Zürich, Switzerland.
5
Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO.
6
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY.
7
New York State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY.
8
Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO.
9
Division of Newborn Medicine, Department of Medicine, Children's Hospital and Harvard Medical School, Boston, MA xianhua.piao@childrens.harvard.edu.
10
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO monk@ohsu.edu.

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.

PMID:
29367382
PMCID:
PMC5839751
DOI:
10.1084/jem.20161714
[Indexed for MEDLINE]
Free PMC Article

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