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

Oligodendrocytes are vulnerable to genetic and environmental insults and its injury leads to demyelinating diseases. The roles of ErbB receptors in maintaining 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 inflammatory 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 tracing the differentiation states of cells expressing tTA/rtTA-dependent transgene or pulse-labeled reporter proteins in vitro and in vivo, we found that Plp-tTA targeted mainly mature oligodendrocytes (MOs), whereas Sox10+/rtTA targeted OPCs and newly-formed oligodendrocytes. The distinct phenotypes of mice with ErbB overactivation induced by Plp-tTA and Sox10+/rtTA consolidated their non-overlapping targeting preferences in the oligodendrocyte lineage, and enabled us to demonstrate that ErbB overactivation in MOs induced necroptosis that caused inflammatory demyelination, whereas in OPCs induced apoptosis that caused non-inflammatory hypomyelination. Early interference with aberrant ErbB activation ceased oligodendrocyte deaths and restored myelin development in both mice. This study suggests that aberrant ErbB activation is an upstream pathogenetic mechanism of demyelinating diseases, providing a potential therapeutic target. SIGNIFICANCE STATEMENT Primary oligodendropathy is one of the etiological mechanisms for multiple sclerosis, and oligodendrocyte necroptosis is a pathological hallmark in the disease. Moreover, the demyelinating disease is now a broad concept that embraces schizophrenia, in which white matter lesions are an emerging feature. ErbB overactivation has been implicated in schizophrenia by genetic analysis and postmortem studies. This study suggests the etiological implications of ErbB overactivation in myelin pathogenesis and elucidates the pathogenetic mechanisms.