KIAA1199: A novel regulator of MEK/ERK-induced Schwann cell dedifferentiation

Glia. 2017 Oct;65(10):1682-1696. doi: 10.1002/glia.23188. Epub 2017 Jul 12.

Abstract

The molecular mechanisms that regulate Schwann cell (SC) plasticity and the role of the Nrg1/ErbB-induced MEK1/ERK1/2 signalling pathway in SC dedifferentiation or in myelination remain unclear. It is currently believed that different levels of MEK1/ERK1/2 activation define the state of SC differentiation. Thus, the identification of new regulators of MEK1/ERK1/2 signalling could help to decipher the context-specific aspects driving the effects of this pathway on SC plasticity. In this perspective, we have investigated the potential role of KIAA1199, a protein that promotes ErbB and MEK1/ERK1/2 signalling in cancer cells, in SC plasticity. We depleted KIAA1199 in the SC-derived MSC80 cell line with RNA-interference-based strategy and also generated Tamoxifen-inducible and conditional mouse models in which KIAA1199 is inactivated through homologous recombination, using the Cre-lox technology. We show that the invalidation of KIAA1199 in SC decreases the expression of cJun and other negative regulators of myelination and elevates Krox20, driving them towards a pro-myelinating phenotype. We further show that in dedifferentiation conditions, SC invalidated for KIAA1199 exhibit lower myelin clearance as well as increased myelination capacity. Finally, the Nrg1-induced activation of the MEK/ERK/1/2 pathway is severely reduced when KIAA1199 is absent, indicating that KIAA1199 promotes Nrg1-dependent MEK1 and ERK1/2 activation in SCs. In conclusion, this work identifies KIAA1199 as a novel regulator of MEK/ERK-induced SC dedifferentiation and contributes to a better understanding of the molecular control of SC dedifferentiation.

Keywords: CEMIP; PNS injury; differentiation; myelin; neuregulin.

MeSH terms

  • Animals
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology*
  • Disease Models, Animal
  • Embryo, Mammalian
  • Ganglia, Spinal / cytology
  • Hedgehog Proteins / genetics
  • Hedgehog Proteins / metabolism
  • Hyaluronoglucosaminidase
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Myelin Proteolipid Protein / genetics
  • Myelin Proteolipid Protein / metabolism
  • Neuregulin-1 / metabolism
  • Neurons / physiology
  • Neurons / ultrastructure
  • Proteins / genetics
  • Proteins / metabolism*
  • Psychomotor Performance / physiology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Recovery of Function / drug effects
  • Recovery of Function / genetics
  • Schwann Cells / physiology*
  • Schwann Cells / ultrastructure
  • Sciatic Neuropathy / etiology
  • Sciatic Neuropathy / genetics
  • Sciatic Neuropathy / physiopathology

Substances

  • Bacterial Proteins
  • Hedgehog Proteins
  • Luminescent Proteins
  • Myelin Proteolipid Protein
  • Neuregulin-1
  • Nrg1 protein, mouse
  • Plp1 protein, mouse
  • Proteins
  • RNA, Small Interfering
  • yellow fluorescent protein, Bacteria
  • CEMIP protein, human
  • Hyaluronoglucosaminidase