Sustained ErbB activation causes demyelination and hypomyelination by driving necroptosis of mature oligodendrocytes and apoptosis of oligodendrocyte precursor cells

Xu Hu, Guanxiu Xiao, Li He, Xiaojie Niu, Huashun Li, Qi Xu, Zhengdong Wei, Mengsheng Qiu, Kenji F. Tanaka, Ying Shen, Yanmei Tao

Research output: Contribution to journalArticlepeer-review

Abstract

Oligodendrocytes are vulnerable to genetic and environmental insults and its injury leads to demyelinating diseases. The roles of ErbB receptors in the CNS myelin integrity are largely unknown. Here we overactivate ErbB receptors that mediate signaling of either neuregulin or EGF family growth factors and found their synergistic activation caused deleterious outcomes in white matter. Sustained ErbB activation induced by the tetracycline-dependent mouse tool Plp-tTA resulted in demyelination, axonal degeneration, oligodendrocyte precursor cell (OPC) proliferation, astrogliosis, and microgliosis in white matter. Moreover, there was hypermyelination prior to these pathological events. In contrast, sustained ErbB activation induced by another tetracycline-dependent mouse tool Sox10+/rtTA caused hypomyelination in the corpus callosum and optic nerve, which appeared to be a developmental deficit and did not associate with OPC regeneration, astrogliosis, or microgliosis. By analyzing the differentiation states of cells that were pulse-labeled with a viral reporter, we found that, during juvenile to adolescent development, Plp-tTA targeted mainly mature oligodendrocytes (MOs), while Sox10+/rtTA targeted OPCs and newly-formed oligodendrocytes. The distinct phenotypes of mice with ErbB overactivation induced by Plp-tTA and Sox10+/rtTA supported the reporter pulse-labeling results, and consolidated their non-overlapping targeting preferences in the oligodendrocyte lineage after early development. These features enabled us to demonstrate that ErbB overactivation in MOs induced necroptosis that caused pathological demyelination, whereas in OPCs induced apoptosis that caused developmental hypomyelination. These results established an upstream pathogenic role of ErbB overactivation in oligodendrocytes, providing molecular and cellular insights into the primary oligodendropathy in demyelinating diseases.

Original languageEnglish
JournalUnknown Journal
DOIs
Publication statusPublished - 2020 Nov 11

Keywords

  • Apoptosis
  • Demyelinating disease
  • ErbB signaling
  • Necroptosis
  • Oligodendropathy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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