A mouse model of tuberous sclerosis: Neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival
A mouse model of tuberous sclerosis: Neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival
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DOI：
10.1523/jneurosci.5540-06.2007
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发表时间：
2007-05-23
影响因子：
5.3
通讯作者：
Kwiatkowski, David J.
中科院分区：
文献类型：
--
作者：
Meikle, Lynsey;Talos, Delia M.;Kwiatkowski, David J.
结节性硬化症 (TSC) 是一种由 TSC1 或 TSC2 突变引起的错构瘤综合征，其中大脑皮质结节和癫痫发作是主要的临床问题。我们改造了小鼠，其中大多数皮层神经元在胚胎发育过程中失去了 Tsc1 表达。这些 Tsc1 突变小鼠从出生后第 5 天开始表现出多种神经系统异常，随后无法生长，中位生存期为 35 天。小鼠还表现出自发和物理刺激下的临床和电图癫痫发作，并且一些癫痫发作以致命的强直阶段结束。在 Tsc1 突变小鼠中，许多皮质和海马神经元增大和/或发育不良，强烈表达磷酸-S6，并且在皮质和海马的多个位点异位。突变小鼠的髓鞘形成明显延迟，这似乎是由诱导性神经元缺陷引起的。这种新的 TSC 大脑模型复制了人类 TSC 大脑损伤的几个特征，并暗示了 Tsc1/Tsc2 在神经元发育中的重要功能。
Tuberous sclerosis ( TSC) is a hamartoma syndrome caused by mutations in TSC1 or TSC2 in which cerebral cortical tubers and seizures are major clinical issues. We have engineered mice in which most cortical neurons lose Tsc1 expression during embryonic development. These Tsc1 mutant mice display several neurological abnormalities beginning at postnatal day 5 with subsequent failure to thrive and median survival of 35 d. The mice also display clinical and electrographic seizures both spontaneously and with physical stimulation, and some seizures end in a fatal tonic phase. Many cortical and hippocampal neurons are enlarged and/or dysplastic in the Tsc1 mutant mice, strongly express phospho-S6, and are ectopic in multiple sites in the cortex and hippocampus. There is a striking delay in myelination in the mutant mice, which appears to be caused by an inductive neuronal defect. This new TSC brain model replicates several features of human TSC brain lesions and implicates an important function of Tsc1/Tsc2 in neuronal development.