mTOR signaling in neural stem cells: from basic biology to disease

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.

Fig. 1

mTOR complexes and mTOR signaling network. Selected components and functions of both mTORC1 and mTORC2 complexes are described. Growth factors such as insulin/IGF1 stimulate mTORC1 via the AKT-PI3K and Ras-ERK pathways and mTORC2 via unknown pathways. AKT- and ERK-mediated phosphorylations inhibit TSC2, a GTPase-activating protein for Rheb, thus activating mTORC1. By contrast, low energy status negatively regulates mTORC1 via AMPK. TSC2 also positively regulates the activity of mTORC2. Feedback loops by S6K1-IRS1 and mTORC1-Grb10 dampen AKT-PI3K signaling

Fig. 2

Developmental scheme depicting tuber and SEN formation in NSC-targeted mouse models. A somatic Emx1-Cre-mediated Tsc1/2 gene mutation, occurring in a fraction of neuroepithelial progenitors (NEPs) (red circles), localized in the dorsal telencephalon (DT) and carrying a germline Tsc1/2 gene mutation (green circles), causes loss of heterozygosity (LOH) and activates a series of events eventually responsible for the development of cortical abnormalities and subependymal nodule (SEN)-like lesions (black arrows). LOH in NEPs leads to enhanced cell proliferation of radial glial cells (RGCs), which might also be promoted directly by hGFAP-Cre-mediated Tsc1/2 loss in RGCs (red arrows). Both Emx1- and hGFAP-Cre-mediated LOH ends up in the production of a progeny of cells with biallelic mutations that abnormally migrate into the embryonic cortex and undergo aberrant differentiation leading to cortical disturbances (blue cells). Notably, only Emx1-Cre-mediated Tsc1 LOH (black arrows) results in the formation of SEN-like periventricular lesions (orange and brown cells) in the late fetal/perinatal ventricular/subventricular zone (VZ/SVZ). Postnatally, SENs are generated by inducible Nestin-CreERT2 recombination in SVZ neural stem cells (NSCs) (orange arrows). V ventricle, DT ventral telencephalon, VT ventral telencephalon