Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin.
Neuronal and glia abnormalities in Tsc1-deficient forebrain and partial rescue by rapamycin.
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DOI：
10.1016/j.nbd.2011.08.024
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发表时间：
2012-01
影响因子：
6.1
通讯作者：
Ess, Kevin C.
中科院分区：
文献类型：
--
作者：
Carson, Robert P.;Van Nielen, Dominic L.;Winzenburger, Peggy A.;Ess, Kevin C.
结节性硬化症（TSC）是一种多器官遗传性疾病，其显著特征是脑畸形（结节），许多患者患有癫痫和自闭症。这些畸形通常表现为神经元和神经胶质细胞异常，可能是TSC中许多神经系统疾病的基础。块茎的发病机制仍然知之甚少，尽管在TSC中mTORC1信号通路的上调已被一致证实。在这里，我们通过灭活小鼠胚胎神经祖细胞中的Tsc1基因来解决TSC脑发育异常。这种策略允许评估Tsc1基因在神经元和胶质细胞系中的作用。Tsc1Emx1-Cre条件敲除（CKO）动物在25天内死亡。他们的大脑体积增大，大脑皮层中含有显著的大细胞，这些细胞大大增加了mTORC1信号，减少了mTORC2信号。皮质层状缺损严重，畸形星形胶质细胞增大，髓鞘增生减少。然后用雷帕霉素治疗Tsc1Emx1-Cre CKO小鼠，看看是否可以挽救过早死亡和大脑异常。产后雷帕霉素治疗完全预防了过早死亡，并在很大程度上逆转了胶质细胞病理，但没有异常的神经元层压。这些发现支持了一个模型，即胚胎神经祖细胞中TSC基因功能的丧失导致TSC患者皮质畸形。雷帕霉素的显著作用表明，即使存在广泛的多谱系异常，TSC患者也可能存在产后治疗窗口期。
Tuberous Sclerosis Complex (TSC) is a multiorgan genetic disease that prominently features brain malformations (tubers) with many patients suffering from epilepsy and autism. These malformations typically exhibit neuronal as well as glial cell abnormalities and likely underlie much of the neurological morbidity seen in TSC. Tuber pathogenesis remains poorly understood though upregulation of the mTORC1 signaling pathway in TSC has been consistently demonstrated. Here we address abnormal brain development in TSC by inactivating the mouse Tsc1 gene in embryonic neural progenitor cells. This strategy permits evaluation of the role of the Tsc1 gene in both neuronal as well as glial cell lineages. Tsc1Emx1-Cre conditional knockout (CKO) animals die by 25 days of life. Their brains have increased size and contain prominent large cells within the cerebral cortex that have greatly increased mTORC1 signaling and decreased mTORC2 signaling. Severe defects of cortical lamination, enlarged dysmorphic astrocytes and decreased myelination were also found. Tsc1Emx1-Cre CKO mice were then treated with rapamycin to see if the premature death and brain abnormalities can be rescued. Postnatal rapamycin treatment completely prevented premature death and largely reversed the glia pathology but not abnormal neuronal lamination. These findings support a model that loss of function of the TSC genes in embryonic neural progenitor cells causes cortical malformations in patients with TSC. The dramatic effect of rapamycin suggests that even with extensive multi-lineage abnormalities, a postnatal therapeutic window may exist for patients with TSC.
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影响因子：
2.2
作者：
Boer, K.;Jansen, F.;Aronica, E.
通讯作者：
Aronica, E.
影响因子：
5.3
作者：
Dibble, Christian C.;Asara, John M.;Manning, Brendan D.
通讯作者：
Manning, Brendan D.
影响因子：
9.9
作者：
Ess, KC;Kamp, CA;Gutmann, DH
通讯作者：
Gutmann, DH
DOI：
10.1073/pnas.151033798
发表时间：
2001-07-17
影响因子：
11.1
作者：
Kobayashi, T;Minowa, O;Hino, O
通讯作者：
Hino, O
影响因子：
3.9
作者：
Huang J;Manning BD
通讯作者：
Manning BD