GPR56/ADGRG1 regulates development and maintenance of peripheral myelin

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytoskeleton / genetics
  • GTP-Binding Protein alpha Subunits, G12-G13 / metabolism
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • Mice, Inbred C57BL
  • Mutation / genetics
  • Myelin Sheath / metabolism*
  • Myelin Sheath / ultrastructure
  • Plectin / metabolism
  • Protein Binding
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, G-Protein-Coupled / physiology
  • Schwann Cells / metabolism
  • Sciatic Nerve / metabolism
  • Signal Transduction
  • Zebrafish
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / physiology*
  • rhoA GTP-Binding Protein / metabolism


  • ADGRG1 protein, human
  • GPR56 protein, mouse
  • Plectin
  • Receptors, G-Protein-Coupled
  • Zebrafish Proteins
  • adgrg1 protein, zebrafish
  • GTP-Binding Protein alpha Subunits, G12-G13
  • rhoA GTP-Binding Protein

Associated data

  • PIR/615752