Sustained ErbB Activation Causes Demyelination and Hypomyelination by Driving Necroptosis of Mature Oligodendrocytes and Apoptosis of Oligodendrocyte Precursor Cells.
Sustained ErbB Activation Causes Demyelination and Hypomyelination by Driving Necroptosis of Mature Oligodendrocytes and Apoptosis of Oligodendrocyte Precursor Cells.
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ErbB 持续激活通过驱动成熟少突胶质细胞坏死性凋亡和少突胶质细胞前体细胞凋亡导致脱髓鞘和低髓鞘形成
DOI：
10.1523/jneurosci.2922-20.2021
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发表时间：
2021-12-01
期刊：
影响因子：
--
通讯作者：
Tao Y
中科院分区：
文献类型：
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作者：
Hu X;Xiao G;He L;Niu X;Li H;Lou T;Hu Q;Yang Y;Xu Q;Wei Z;Qiu M;Tanaka KF;Shen Y;Tao Y
少突胶质细胞易受遗传和环境损伤，其损伤导致脱髓鞘疾病。ErbB受体在维持CNS髓鞘完整性中的作用在很大程度上是未知的。在这里，我们过度激活ErbB受体，介导神经调节蛋白（NRG）或表皮生长因子（EGF）家族生长因子的信号传导，并发现它们的协同激活导致白色物质的有害结果。由四环素依赖性小鼠工具Plp-tTA诱导的持续ErbB活化导致白色物质中的脱髓鞘、轴突变性、少突胶质细胞前体细胞（OPC）增殖、星形胶质细胞增生和小胶质细胞增生。此外，在这些炎症病理事件之前存在髓鞘过度形成。相反，另一种四环素依赖性小鼠工具Sox 10 +/rtTA诱导的持续ErbB激活导致胼胝体和视神经的髓鞘形成不足，这似乎是一种发育缺陷，与OPC再生、星形胶质细胞增生或小胶质细胞增生无关。通过跟踪表达四环素控制的转录激活因子（tTA）/反向tTA（rtTA）依赖性转基因或脉冲标记报告蛋白的细胞在体外和体内的分化状态，我们发现Plp-tTA主要靶向成熟的少突胶质细胞（MO），而Sox 10 +/rtTA靶向OPC和新形成的少突胶质细胞（NFOs）。Plp-tTA和Sox 10 +/rtTA诱导ErbB过度激活的小鼠的不同表型巩固了它们在少突胶质细胞谱系中的非重叠靶向偏好，并使我们能够证明MO中ErbB过度激活诱导坏死性凋亡，导致炎性脱髓鞘，而OPCs诱导凋亡，导致非炎性髓鞘形成不足。早期干预异常ErbB激活停止少突胶质细胞死亡和恢复髓鞘发育的小鼠。本研究提示ErbB异常激活是脱髓鞘疾病的上游发病机制，为治疗脱髓鞘疾病提供了一个潜在的靶点。原发性少突胶质细胞病是多发性硬化症的病因机制之一，少突胶质细胞坏死是该病的病理标志。此外，脱髓鞘疾病现在是一个广泛的概念，包括精神分裂症，其中白色物质病变是一个新兴的特点。ErbB过度激活已被牵连在精神分裂症的遗传分析和尸检研究。本研究提示ErbB过度激活在髓鞘病变中的病因学意义，并阐明其发病机制。
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 (NRG) or epidermal growth factor (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 before these inflammatory pathologic 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 tetracycline-controlled transcriptional activator (tTA)/reverse 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 (NFOs). The distinct phenotypes of mice with ErbB overactivation induced by Plp-tTA and Sox10+/rtTA consolidated their nonoverlapping 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 noninflammatory 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 etiologic mechanisms for multiple sclerosis, and oligodendrocyte necroptosis is a pathologic 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 etiologic implications of ErbB overactivation in myelin pathogenesis and elucidates the pathogenetic mechanisms.