mTOR signaling in neural stem cells: from basic biology to disease
- PDF / 426,685 Bytes
- 12 Pages / 595.276 x 790.866 pts Page_size
- 91 Downloads / 179 Views
Cellular and Molecular Life Sciences
REVIEW
mTOR signaling in neural stem cells: from basic biology to disease Laura Magri • Rossella Galli
Received: 24 June 2012 / Revised: 27 September 2012 / Accepted: 15 October 2012 / Published online: 4 November 2012 Ó Springer Basel 2012
Abstract 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. Keywords mTOR Neural stem cells Tuberous sclerosis complex
L. Magri R. Galli (&) Neural Stem Cell Biology Unit, Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Scientific Institute, Via Olgettina 58, 20132 Milan, Italy e-mail: [email protected]
Introduction Over the past few years, the mammalian target of rapamycin (mTOR) pathway has gained much attention as it represents a pivotal cellular ‘‘hub’’, integrating many different inputs, like nutrients, growth factors, and cellular energy status [1]. As such, it finely regulates different catabolic and anabolic processes that cooperatively govern cell growth and metabolism. Due to its multiplicity of outputs and functions, mTOR is deregulated in many diseases, including cancer, metabolic syndromes, and genetic disorders [2, 3]. Notably, mTOR signaling has been recently involved in the control of the homeostasis of several distinct stem cell compartments [4–7]. Specifically, hyperactivation of mTOR in neural stem cells (NSCs) has been etiologically correlated to the onset of the neuropathological lesions that are associated with tuberous sclerosis complex (TSC) [8, 9]. Indeed, the TSC-mTOR pathway plays an essential role in the maintenance and in vivo functions of both NSCs and their neuronal progeny by critically regulating selfrenewal, multilineage differentiation, and terminal maturation. Complete inhibition of mTORC1 activity in normal NSCs results in the same phenotype observed by the hyperactivation of the same pathway by Tsc1 loss, i.e., decreased self-renewal and abrogation of neuron generation [8].
Data Loading...
