Meikle Lynsey, Talos Delia M, Onda Hiroaki, Pollizzi Kristen, Rotenberg Alexander, Sahin Mustafa, Jensen Frances E, Kwiatkowski David J
Division of Translational Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
J Neurosci. 2007 May 23;27(21):5546-58. doi: 10.1523/JNEUROSCI.5540-06.2007.
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.
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临床问题。我们构建了在胚胎发育期间大多数皮质神经元失去Tsc1表达的小鼠。这些Tsc1突变小鼠在出生后第5天开始出现多种神经学异常，随后生长发育不良，中位生存期为35天。这些小鼠还会自发地以及在物理刺激下出现临床和脑电图癫痫发作，一些癫痫发作会以致命的强直期告终。在Tsc1突变小鼠中，许多皮质和海马神经元增大和/或发育异常，强烈表达磷酸化S6，并且在皮质和海马的多个部位异位。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脑模型复制了人类TSC脑损伤的几个特征，并暗示Tsc1/Tsc2在神经元发育中具有重要功能。
