Neural Stem Cell Biology Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Via Olgettina 58, Milan, Italy.
Cell Mol Life Sci. 2013 Aug;70(16):2887-98. doi: 10.1007/s00018-012-1196-x. Epub 2012 Nov 4.
The mammalian target of rapamycin (mTOR) pathway is a central controller of growth and homeostasis, and, as such, is implicated in disease states where growth is deregulated, namely cancer, metabolic diseases, and hamartoma syndromes like tuberous sclerosis complex (TSC). Accordingly, mTOR is also a pivotal regulator of the homeostasis of several distinct stem cell pools in which it finely tunes the balance between stem cell self-renewal and differentiation. mTOR hyperactivation in neural stem cells (NSCs) has been etiologically linked to the development of TSC-associated neurological lesions, such as brain hamartomas and benign tumors. Animal models generated by deletion of mTOR upstream regulators in different types of NSCs reproduce faithfully some of the TSC neurological alterations. Thus, mTOR dysregulation in NSCs seems to be responsible for the derangement of their homeostasis, thus leading to TSC development. Here we review recent advances in the molecular dissection of the mTOR cascade, its involvement in the maintenance of stem cell compartments, and in particular the implications of mTOR hyperactivation in NSCs in vivo and in vitro.
哺乳动物雷帕霉素靶蛋白（mTOR）途径是生长和体内平衡的中央控制器，因此，它与生长失调的疾病状态有关，即癌症、代谢疾病和结节性硬化症（TSC）等错构瘤综合征。因此，mTOR 也是几个不同的干细胞池的稳态的关键调节剂，它可以精细地调节干细胞自我更新和分化之间的平衡。神经干细胞（NSC）中 mTOR 的过度激活与 TSC 相关的神经病变的发展有关，如脑错构瘤和良性肿瘤。通过在不同类型的 NSCs 中删除 mTOR 上游调节剂生成的动物模型忠实地再现了 TSC 的一些神经改变。因此，NSC 中 mTOR 的失调似乎负责它们的体内平衡失调，从而导致 TSC 的发展。在这里，我们回顾了 mTOR 级联反应的分子解析、其在干细胞区室维持中的作用，以及 mTOR 在体内和体外 NSCs 中的过度激活的影响的最新进展。
