Biozentrum, University of Basel, CH-4056 Basel, Switzerland.
J Neurosci. 2013 May 1;33(18):7799-810. doi: 10.1523/JNEUROSCI.3294-12.2013.
The mammalian target of rapamycin (mTOR) regulates cell growth in response to various intracellular and extracellular signals. It assembles into two multiprotein complexes: the rapamycin-sensitive mTOR complex 1 (mTORC1) and the rapamycin-insensitive mTORC2. In this study, we inactivated mTORC1 in mice by deleting the gene encoding raptor in the progenitors of the developing CNS. Mice are born but never feed and die within a few hours. The brains deficient for raptor show a microcephaly starting at E17.5 that is the consequence of a reduced cell number and cell size. Changes in cell cycle length during late cortical development and increased cell death both contribute to the reduction in cell number. Neurospheres derived from raptor-deficient brains are smaller, and differentiation of neural progenitors into glia but not into neurons is inhibited. The differentiation defect is paralleled by decreased Stat3 signaling, which is a target of mTORC1 and has been implicated in gliogenesis. Together, our results show that postnatal survival, overall brain growth, and specific aspects of brain development critically depend on mTORC1 function.
哺乳动物雷帕霉素靶蛋白（mTOR）可响应各种细胞内和细胞外信号来调节细胞生长。它组装成两个多蛋白复合物：雷帕霉素敏感的 mTOR 复合物 1（mTORC1）和雷帕霉素不敏感的 mTORC2。在这项研究中，我们通过删除发育中中枢神经系统祖细胞中编码 raptor 的基因使 mTORC1 在小鼠中失活。出生后的小鼠从不进食，并在数小时内死亡。缺乏 raptor 的大脑表现出从 E17.5 开始的小头畸形，这是细胞数量和细胞大小减少的结果。晚期皮质发育过程中细胞周期长度的变化以及细胞死亡的增加都导致细胞数量减少。来自缺乏 raptor 的大脑的神经球较小，神经祖细胞向胶质分化而不是向神经元分化受到抑制。分化缺陷伴随着 Stat3 信号的降低，Stat3 信号是 mTORC1 的靶标，并且与神经发生有关。总之，我们的结果表明，出生后存活、大脑整体生长以及大脑发育的特定方面都严重依赖于 mTORC1 的功能。
