Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2
Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2
复制标题
DOI：
10.1038/nn1566
复制
发表时间：
2005-12-01
影响因子：
25
通讯作者：
Sabatini, BL
中科院分区：
文献类型：
--
作者：
Tavazoie, SF;Alvarez, VA;Sabatini, BL
肿瘤抑制基因TSC1或TSC2的突变导致结节性硬化症（TSC），这是一种显性错构瘤性疾病，通常表现为精神发育迟滞、癫痫和自闭症。这些神经系统症状的病因尚不清楚，神经元中TSC通路的功能也未知。我们发现，在有丝分裂后，小鼠和大鼠的海马锥体神经元，Tsc 1或Tsc 2的损失引发扩大的胞体和树突棘，并改变了突触的特性。此外，Tsc1基因单拷贝的丢失足以扰乱树突棘结构。形态学的变化需要调节肌动蛋白解聚因子cofilin在一个保守的LIM激酶磷酸化位点，其磷酸化增加的损失TSC2。因此，TSC途径调节神经元中的生长和突触功能，并且神经元结构和功能的扰动可能有助于TSC的神经症状的发病机制。
Mutations in the TSC1 or TSC2 tumor suppressor genes lead to tuberous sclerosis complex (TSC), a dominant hamartomatous disorder that often presents with mental retardation, epilepsy and autism. The etiology of these neurological symptoms is unclear and the function of the TSC pathway in neurons is unknown. We found that in post-mitotic, hippocampal pyramidal neurons of mice and rats, loss of Tsc1 or Tsc2 triggered enlargement of somas and dendritic spines and altered the properties of glutamatergic synapses. Furthermore, loss of a single copy of the Tsc1 gene was sufficient to perturb dendritic spine structure. Morphological changes required regulation of the actin-depolymerization factor cofilin at a conserved LIM-kinase phosphorylation site, the phosphorylation of which was increased by loss of Tsc2. Thus, the TSC pathway regulates growth and synapse function in neurons, and perturbations of neuronal structure and function are likely to contribute to the pathogenesis of the neurological symptoms of TSC.