Neuronal ADAM10 Promotes Outgrowth of Small-Caliber Myelinated Axons in the Peripheral Nervous System

J Neuropathol Exp Neurol. 2015 Nov;74(11):1077-85. doi: 10.1097/NEN.0000000000000253.

Abstract

The regulation of myelination and axonal outgrowth in the peripheral nervous system is controlled by a complex signaling network involving various signaling pathways. Members of the A Disintegrin And Metalloproteinase (ADAM) family are membrane-anchored proteinases with both proteolytic and disintegrin characteristics that modulate the function of signaling molecules. One family member, ADAM17, is known to influence myelination by cleaving and thus regulating one of the key signals, neuregulin-1, which controls peripheral nervous system myelination. A similar function for ADAM10 had been suggested by previous in vitro studies. Here, we assessed whether ADAM10 exerts a similar function in vivo and deleted ADAM10 in a cell type-specific manner in either neurons or Schwann cells. We found that ADAM10 is not required in either Schwann cells or neurons for normal myelination during development or for remyelination after injury. Instead, ADAM10 is required specifically in neurons for the outgrowth of myelinated small-fiber axons in vitro and after injury in vivo. Thus, we report for the first time a neuron-intrinsic function of ADAM10 in axonal regeneration that is distinct from that of the related protein family member ADAM17 and that may have implications for targeting ADAM function in nervous system diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / deficiency*
  • ADAM Proteins / genetics
  • ADAM10 Protein
  • Action Potentials / genetics
  • Amyloid Precursor Protein Secretases / deficiency*
  • Amyloid Precursor Protein Secretases / genetics
  • Animals
  • Axons / physiology*
  • Disease Models, Animal
  • Ganglia, Spinal / cytology
  • Hand Strength / physiology
  • In Vitro Techniques
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics
  • Mice
  • Mice, Transgenic
  • Microscopy, Electron
  • Motor Neurons / cytology*
  • Nerve Fibers, Myelinated / physiology*
  • Nerve Regeneration / genetics*
  • Neural Conduction / genetics
  • Organ Culture Techniques
  • Peripheral Nervous System / cytology*
  • Peripheral Nervous System / physiology
  • Sciatic Nerve / pathology
  • Sciatic Nerve / ultrastructure
  • Sciatic Neuropathy / genetics
  • Sciatic Neuropathy / pathology
  • Sciatic Neuropathy / physiopathology

Substances

  • Membrane Proteins
  • Amyloid Precursor Protein Secretases
  • ADAM Proteins
  • ADAM10 Protein
  • Adam10 protein, mouse