Kwon Chang-Hyuk, Zhu Xiaoyan, Zhang Junyuan, Baker Suzanne J
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
Proc Natl Acad Sci U S A. 2003 Oct 28;100(22):12923-8. doi: 10.1073/pnas.2132711100. Epub 2003 Oct 8.
The mechanisms that regulate mammalian cell size during development and homeostatic maintenance are poorly understood. The tumor suppressor Pten is required for correct maintenance of mammalian neuronal soma size. Selective inactivation of Pten in postnatal granule neurons of the cerebellum and dentate gyrus in mouse causes cell-autonomous hypertrophy as well as more complex phenotypes, including progressive macrocephaly, seizures, and premature death. To determine the contribution of mTor signaling to Pten-mediated growth regulation in the mammalian nervous system, we treated Pten conditional knockout mice with CCI-779, a specific mTor inhibitor. mTor inhibition decreased the seizure frequency and death rate in Pten mutant mice, prevented the increase in Pten-deficient neuronal soma size in young mice, and reversed neuronal soma enlargement in adult mice. mTor inhibition did not decrease the size of wild-type adult neurons. Thus, mTor is required for neuronal hypertrophy downstream of Pten deficiency, but is not required for maintenance of normal neuronal soma size. mTOR inhibitors may be useful therapeutic agents for diseases in brain resulting from PTEN deficiency such as Lhermitte-Duclos disease or glioblastoma multiforme.
在发育和稳态维持过程中调节哺乳动物细胞大小的机制目前仍知之甚少。肿瘤抑制因子Pten是正确维持哺乳动物神经元胞体大小所必需的。在小鼠小脑和齿状回的产后颗粒神经元中选择性失活Pten会导致细胞自主性肥大以及更复杂的表型，包括进行性巨头畸形、癫痫发作和过早死亡。为了确定mTor信号传导在哺乳动物神经系统中对Pten介导的生长调节的作用，我们用特异性mTor抑制剂CCI-779处理Pten条件性敲除小鼠。抑制mTor可降低Pten突变小鼠的癫痫发作频率和死亡率，防止幼鼠中Pten缺陷型神经元胞体大小增加，并逆转成年小鼠神经元胞体的增大。抑制mTor不会减小野生型成年神经元的大小。因此，mTor是Pten缺陷下游神经元肥大所必需的，但维持正常神经元胞体大小则不需要mTor。mTOR抑制剂可能是治疗由PTEN缺乏引起的脑部疾病（如Lhermitte-Duclos病或多形性胶质母细胞瘤）的有用治疗药物。
