Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy.
Genetic disruption of Pten in a novel mouse model of tomaculous neuropathy.
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DOI：
10.1002/emmm.201200227
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发表时间：
2012-06
影响因子：
11.1
通讯作者：
Nave, Klaus-Armin
中科院分区：
文献类型：
--
作者：
Goebbels, Sandra;Oltrogge, Jan H.;Wolfer, Susanne;Wieser, Georg L.;Nientiedt, Tobias;Pieper, Alexander;Ruhwedel, Torben;Groszer, Matthias;Sereda, Michael W.;Nave, Klaus-Armin
“番茄瘤”和髓鞘外展是一组不同的遗传性脱髓鞘神经病变的显著神经病理学特征。而潜在的遗传缺陷是众所周知的，分子机制的形成番茄仍然是不清楚的。我们假设它们是由不受控制的髓鞘膜过度生长引起的，这一过程在正常发育中由神经调节蛋白1/ErbB2、PI3激酶信号和ERK/MAPK信号调节。在这里，我们通过在雪旺细胞中靶向破坏Pten，证明内源性PI3激酶途径的过度激活导致局灶性髓鞘增生、髓鞘外翻和瘤状突起，即使在成年动物中被他莫昔芬诱导，也与进行性周围神经病变有关。活化的AKT激酶与旁神经环和Schmidt-Lanterman切口的PtdIns(3,4,5)P3相关。这种具有人类CMT 4B1型和HNPP特征的髓磷脂病理学依赖于AKT/mTOR信号传导，经雷帕霉素治疗的小鼠病理学显著改善证明了这一点。我们认为，非致密髓磷脂区域受到PTEN的终身保护，以防止异常的膜生长，磷酸化肌肽水平失调在肿瘤神经病变的病理中起关键作用。
‘Tomacula’ and myelin outfoldings are striking neuropathological features of a diverse group of inherited demyelinating neuropathies. Whereas the underlying genetic defects are well known, the molecular mechanisms of tomacula formation have remained obscure. We hypothesized that they are caused by uncontrolled, excessive myelin membrane growth, a process, which is regulated in normal development by neuregulin-1/ErbB2, PI3 Kinase signalling and ERK/MAPK signalling. Here, we demonstrate by targeted disruption of Pten in Schwann cells that hyperactivation of the endogenous PI3 Kinase pathway causes focal hypermyelination, myelin outfoldings and tomacula, even when induced in adult animals by tamoxifen, and is associated with progressive peripheral neuropathy. Activated AKT kinase is associated with PtdIns(3,4,5)P3 at paranodal loops and Schmidt–Lanterman incisures. This striking myelin pathology, with features of human CMT type 4B1 and HNPP, is dependent on AKT/mTOR signalling, as evidenced by a significant amelioration of the pathology in mice treated with rapamycin. We suggest that regions of non-compact myelin are under lifelong protection by PTEN against abnormal membrane outgrowth, and that dysregulated phosphoinositide levels play a critical role in the pathology of tomaculous neuropathies.
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影响因子：
7.8
作者：
Genoud, Stephane;Lappe-Siefke, Corinna;Goebbels, Sandra;Radtke, Freddy;Aguet, Michel;Scherer, Steven S;Suter, Ueli;Nave, Klaus-Armin;Mantei, Ned
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