Betacellulin regulates schwann cell proliferation and myelin formation in the injured mouse peripheral nerve

Glia. 2017 Apr;65(4):657-669. doi: 10.1002/glia.23119. Epub 2017 Jan 31.


When a nerve fiber is cut or crushed, the axon segment that is separated from the soma degenerates distal from the injury in a process termed Wallerian degeneration (WD). C57BL/6OlaHsd-WldS (WldS ) mutant mice exhibit significant delays in WD. This results in considerably delayed Schwann cell and macrophage responses and thus in impaired nerve regenerations. In our previous work, thousands of genes were screened by DNA microarrays and over 700 transcripts were found to be differentially expressed in the injured sciatic nerve of WldS compared with wild-type (WT) mice. One of these transcripts, betacellulin (Btc), was selected for further analysis since it has yet to be characterized in the nervous system, despite being known as a ligand of the ErbB receptor family. We show that Btc mRNA is strongly upregulated in immature and dedifferentiated Sox2+ Schwann cells located in the sciatic nerve distal stump of WT mice, but not WldS mutants. Transgenic mice ubiquitously overexpressing Btc (Tg-Btc) have increased numbers of Schmidt-Lantermann incisures compared with WT mice, as revealed by Coherent anti-Stokes Raman scattering (CARS). Tg-Btc mice also have faster nerve conduction velocity. Finally, we found that deficiency in Btc reduces the proliferation of myelinating Schwann cells after sciatic nerve injury, while Btc overexpression induces Schwann cell proliferation and improves recovery of locomotor function. Taken together, these results suggest a novel regulatory role of Btc in axon-Schwann cell interactions involved in myelin formation and nerve repair. GLIA 2017 GLIA 2017;65:657-669.

Keywords: ErbB receptor; Schmidt-Lantermann incisure; Schwann cells; Wallerian degeneration; demyelination; node of Ranvier; peripheral nervous system; remyelination; sciatic nerve injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Betacellulin / genetics
  • Betacellulin / metabolism
  • CD11 Antigens / genetics
  • CD11 Antigens / metabolism
  • Cell Proliferation / genetics*
  • Disease Models, Animal
  • Early Growth Response Protein 2 / metabolism
  • Electric Stimulation
  • Gene Expression Regulation / genetics*
  • In Vitro Techniques
  • Mice
  • Mice, Inbred C57BL
  • Microarray Analysis
  • Myelin Sheath / physiology*
  • Nerve Regeneration / genetics
  • Neural Conduction / genetics
  • Neural Conduction / physiology
  • SOXB1 Transcription Factors / genetics
  • SOXB1 Transcription Factors / metabolism
  • Schwann Cells / physiology*
  • Sciatic Neuropathy / metabolism*
  • Sciatic Neuropathy / pathology*
  • Time Factors


  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Betacellulin
  • Btc protein, mouse
  • CD11 Antigens
  • CD68 antigen, human
  • Early Growth Response Protein 2
  • SOXB1 Transcription Factors
  • Sox2 protein, mouse