Non-cell-autonomous function of DR6 in Schwann cell proliferation

EMBO J. 2018 Apr 3;37(7):e97390. doi: 10.15252/embj.201797390. Epub 2018 Feb 19.


Death receptor 6 (DR6) is an orphan member of the TNF receptor superfamily and controls cell death and differentiation in a cell-autonomous manner in different cell types. Here, we report an additional non-cell-autonomous function for DR6 in the peripheral nervous system (PNS). DR6-knockout (DR6 KO) mice showed precocious myelination in the PNS Using an in vitro myelination assay, we demonstrate that neuronal DR6 acts in trans on Schwann cells (SCs) and reduces SC proliferation and myelination independently of its cytoplasmic death domain. Mechanistically, DR6 was found to be cleaved in neurons by "a disintegrin and metalloprotease 10" (ADAM10), releasing the soluble DR6 ectodomain (sDR6). Notably, in the in vitro myelination assay, sDR6 was sufficient to rescue the DR6 KO phenotype. Thus, in addition to the cell-autonomous receptor function of full-length DR6, the proteolytically released sDR6 can unexpectedly also act as a paracrine signaling factor in the PNS in a non-cell-autonomous manner during SC proliferation and myelination. This new mode of DR6 signaling will be relevant in future attempts to target DR6 in disease settings.

Keywords: ADAM10; DR6; Schwann cell; myelin; shedding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM10 Protein / metabolism*
  • Amyloid Precursor Protein Secretases / metabolism*
  • Animals
  • Cell Death
  • Cell Line
  • Cell Proliferation*
  • Cytoplasm / metabolism
  • Death Domain
  • Disintegrins / metabolism
  • Female
  • HEK293 Cells
  • Humans
  • Hybridomas
  • Male
  • Membrane Proteins / metabolism*
  • Metalloproteases / metabolism
  • Mice
  • Mice, Knockout
  • Myelin Sheath / metabolism
  • Neurons / metabolism*
  • Paracrine Communication
  • Phenotype
  • Receptors, Tumor Necrosis Factor / genetics
  • Receptors, Tumor Necrosis Factor / metabolism*
  • Schwann Cells / metabolism*
  • Schwann Cells / ultrastructure
  • Substrate Specificity


  • Disintegrins
  • Membrane Proteins
  • Receptors, Tumor Necrosis Factor
  • Tnfrsf21 protein, mouse
  • Amyloid Precursor Protein Secretases
  • Metalloproteases
  • ADAM10 Protein
  • Adam10 protein, mouse