ErbB dysregulation impairs cognition via myelination-dependent and - independent oligodendropathy
ErbB dysregulation impairs cognition via myelination-dependent and - independent oligodendropathy
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ErbB 失调通过髓鞘形成依赖性和独立性少突神经病损害认知
DOI：
10.1101/2020.09.09.289223
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Yanmei Tao
中科院分区：
文献类型：
--
作者：
Xu Hu;Guanxiu Xiao;Li He;Qingyu Zhu;Xiaojie Niu;Huashun Li;Qi Xu;Zhengdong Wei;Hao Huang;Yifei Luan;Mengsheng Qiu;Kenji Tanaka;Ying Shen;Yanmei Tao
脑白质异常是精神分裂症的一种新的病理特征。然而，他们与这种疾病的关系在很大程度上仍然难以捉摸。ErbB受体及其配体，其中一些是外周髓鞘形成所必需的，增加了精神分裂症的易感性。通过在早期发育的小鼠中以少突胶质细胞阶段特异性的方式协同操纵ErbB受体的活性，我们展示了ErbB信号对处于不同分化状态的少突胶质细胞的不同影响。在成熟的少突胶质细胞中，ErbB的过度激活会导致坏死性下垂导致脱髓鞘，而在少突胶质前体细胞中，则会诱导细胞凋亡，导致髓鞘减少。相反，抑制ErbB可增加少突胶质前体细胞的增殖，但通过抑制新形成的少突胶质细胞的髓鞘形成能力而诱导髓鞘减少。值得注意的是，在成熟的少突胶质细胞中抑制ErbB降低了能量应激下的轴突传导，并损害了独立于髓鞘病理的工作记忆能力。本研究揭示了ErbB基因异常引起的少突胶质细胞易损性的病因学意义，并阐明了不同结构和功能白质异常的发病机制。
White matter abnormalities are an emerging pathological feature of schizophrenia. However, their attributions to the disease remain largely elusive. ErbB receptors and their ligands, some of which are essential for peripheral myelination, confer susceptibility to schizophrenia. By synergistically manipulating ErbB receptor activities in a oligodendrocyte-stage-specific manner in mice after early development, we demonstrate the distinct effects of ErbB signaling on oligodendrocytes at various differentiation states. ErbB overactivation, in mature oligodendrocytes, induces necroptosis causing demyelination, whereas in oligodendrocyte precursor cells, induces apoptosis causing hypomyelination. In contrast, ErbB inhibition increases oligodendrocyte precursor cell proliferation but induces hypomyelination by suppressing the myelinating capabilities of newly-formed oligodendrocytes. Remarkably, ErbB inhibition in mature oligodendrocytes diminishes axonal conduction under energy stress and impairs working memory capacity independently of myelin pathology. This study reveals the etiological implications of oligodendrocyte vulnerability induced by ErbB dysregulation, and elucidates the pathogenetic mechanisms for variable structural and functional white matter abnormalities.
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影响因子：
25
作者：
Hughes EG;Orthmann-Murphy JL;Langseth AJ;Bergles DE
通讯作者：
Bergles DE
影响因子：
12.7
作者：
Bradl M;Lassmann H
通讯作者：
Lassmann H
影响因子：
16.2
作者：
Brinkmann, Bastian G.;Agarwal, Amit;Sereda, Michael W.;Garratt, Alistair N.;Mueller, Thomas;Wende, Hagen;Stassart, Ruth M.;Nawaz, Schanila;Humml, Christian;Velanac, Viktorija;Radyushkin, Konstantin;Goebbels, Sandra;Fischer, Tobias M.;Franklin, Robin J.;Lai, Cary;Ehrenreich, Hannelore;Birchmeier, Carmen;Schwab, Markus H.;Nave, Klaus Armin
通讯作者：
Nave, Klaus Armin
影响因子：
64.8
作者：
Oberst, Andrew;Dillon, Christopher P.;Weinlich, Ricardo;McCormick, Laura L.;Fitzgerald, Patrick;Pop, Cristina;Hakem, Razq;Salvesen, Guy S.;Green, Douglas R.
通讯作者：
Green, Douglas R.
影响因子：
7.7
作者：
Andrea Trevisiol;Aiman S. Saab;U. Winkler;Grit Marx;H. Imamura;W. Möbius;Kathrin Kusch;K. Nave;J. Hirrlinger
通讯作者：
Andrea Trevisiol;Aiman S. Saab;U. Winkler;Grit Marx;H. Imamura;W. Möbius;Kathrin Kusch;K. Nave;J. Hirrlinger