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Exp Neurobiol 2015; 24(3): 177-185
Published online September 30, 2015
© The Korean Society for Brain and Neural Sciences
Da Yong Lee
Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea
Correspondence to: *To whom correspondence should be addressed.
TEL: 82-42-860-4475, FAX: 82-42-879-8495
mTOR is a serine/threonine kinase composed of multiple protein components. Intracellular signaling of mTOR complexes is involved in many of physiological functions including cell survival, proliferation and differentiation through the regulation of protein synthesis in multiple cell types. During brain development, mTOR-mediated signaling pathway plays a crucial role in the process of neuronal and glial differentiation and the maintenance of the stemness of neural stem cells. The abnormalities in the activity of mTOR and its downstream signaling molecules in neural stem cells result in severe defects of brain developmental processes causing a significant number of brain disorders, such as pediatric brain tumors, autism, seizure, learning disability and mental retardation. Understanding the implication of mTOR activity in neural stem cells would be able to provide an important clue in the development of future brain developmental disorder therapies.
Keywords: mTOR, neurogenesis, gliogenesis, neural stem cell, pediatric brain tumors, brain developmental disorders
Mammalian target of rapamycin (mTOR), complexes, large protein kinases, are composed of multiple protein components. mTOR has been discovered over the late decades showing that its pathways are involved in various human diseases, such as cancer and diabetes, by regulating angiogenesis [1,2], insulin resistance , adipogenesis , and immune cell activation . In various cell types, mTOR shows its critical roles in multiple intracellular functions including mitochondrial metabolism, autophagy, cytoskeleton organization, protein synthesis and lipid metabolism (Fig. 1) [4,6]. Previous works identified two functionally and structurally distinct types of mTOR complexes. Type I mTOR complex (mTORC1) is composed of mTOR, raptor, mLST8, PRAS40 and DEPTOR. mTORC1 has its functions in cell proliferation, growth through the regulation of RNA translation, nutrient metabolism and autophagy (Fig. 1A) [7,8,9,10]. mTORC1 signaling pathway is controlled by the signals from receptor tyrosine kinase-RAS in the brain. Type 2 mTOR complex (mTORC2) is composed of rictor, mSIN1, Protor-1, mLST8 and DEPTOR [6,11]. mTORC2 modulates cell survival and proliferation through the activation of AKT/PKB by direct interaction and the phosphorylation of AKT/PKB on Ser473 . However, the upstream signaling molecule which leads to mTORC2 activation is not well identified so far (Fig. 1B). These two types of mTOR complexes were differentially characterized on the basis of rapamycin sensitivity. Rapamycin is the most well-known inhibitor of mTOR with higher efficiency on mTORC1 compared to mTORC2 . Although detailed regulation mechanisms of mTOR activity are not fully understood in the brain, mTOR signaling pathway and its upstream tumor suppressor genes (
Stem cells have abilities to self-renew, proliferate and differentiate into various lineages of cells (Fig. 2). Maintenance of pluripotency and decision to differentiation in various types of stem cells require very well controlled expression of multiple transcription factors (e.g.
Neuronal differentiation has to be controlled by fine tuning the processes of both spatial and temporal patterning of neurons for normal brain development. The defects in neuronal differentiation result in abnormal neuronal networks in the brain causing serious problems in the functions of cognition, movement and perception. In
Increasing evidence shows that the functions of glial cells are critical for maintaining homeostasis of neurons with important roles in energy metabolite supply  and the clearance of extracellular glutamate [31,32] and potassium , myelination , modulation of neuronal activity and synaptic formation of neurons  in the brain. Abnormal gliogenesis is implicated with astrocytomas and psychiatric disorders. The effects of abnormalities in the function of astrocytes on rett syndrome are very well illustrated the studies using animal models and
Brain developmental disorders are impairments of the growth and the development of CNS organs. Brain diseases caused by developmental abnormalities include neurological disorders, such as autism, dyslexia, epilepsy, ADHD and mental retardation. Besides of these neurological disorders, brain tumors (gliomas, ependymomas and medulloblastomas) also have a close relationship with the abnormalities of brain regional NSC/progenitor cell populations during development in children [13,39,40]. In general, both developmental disorders and pediatric brain tumors are diagnosed in early developmental stages and childhood [41,42,43,44] raising a possibility that the NSC/progenitor cell populations rather than differentiated brain cells could have an implication in disease phenotypes. Although the causing factors of the diseases are not fully uncovered, there are several known genetic factors which are commonly found in the patients with learning disability, autism, epilepsy and pediatric brain tumors. Interestingly, some of tumor suppressor genes, such as
More recently the importance of NSC/progenitor populations has been emphasized in the formation of pediatric brain tumors [39,46]. In many types of pediatric brain tumors, including medulloblastomas, astrocytomas and ependymomas, histologically identical brain tumors are often composed of distinct subtypes which can be separated by their distinct gene expression patterns reflecting their region specific cellular origin, the embryonic brain region NSC/progenitors [39,40,46,47]. Similarly, our previous study shows that brain region specific activation of mTORC2-AKT in brainstem NSCs but not in cortical NSCs with higher rictor in the brainstem compared to neocortex is associated with the spatial patterning of astrogliomas (higher frequency in the brainstem compared to the neocortex) in neurofibromatosis-1 (NF1) . Moreover, previous study shows that the malignant astrocytomas in adult brain are also arisen from the NSCs in the subventricular zone of the lateral ventricle in genetically engineered mouse model . In this regard, the determination of signaling pathways controlling the cellular functions of NSCs is essential for understanding the process of pediatric and adult brain tumor formation. mTORC1 complex is considered as the prime mediator of receptor tyrosine kinase (RTK) signaling through the growth factors, such as EGF and PDGF, regulating self-renewal, proliferation and differentiation in brain NSCs [25,28]. Generally, RTK activation leads to downstream activation of mTOR regulators, including RAS, PTEN, AKT, RHEB and TSC1/2. The mutations of PTEN and TSC 1/2 are often detected in adult and pediatric brain tumors [49,50] (Fig. 3). Although the mutations of AKT and RAS are relatively rare, these signaling molecules can be hyperactivated by the elevation of their positive regulation mechanisms in pediatric brain tumors. In NF1 associated pediatric brain tumors (gliomas), hyperactivation of RAS can be induced by the loss of NF1 tumor suppressor gene which codes neurofibromin, a negative regulator of RAS . Similarly, the elevation of active Akt level can be induced by the loss of PTEN, a negative upstream regulator of Akt, in high grade gliomas . NSC/progenitors are considered as the cellular origin in pediatric gliomas  even though the histology of pediatric gliomas show that tumor contains a significant number of GFAP-positive cells and immune cells as well. The functional defects of mTOR in NSCs are closely implicated to the pediatric gliomagenesis. In NF1 associated pediatric glioma models, loss of
Deregulation of tumor suppressors (
Taken together, the studies reviewed here demonstrate that delicate activity balance of mTOR complexes is essential for both the maintenance of NSC stemness and the differentiation into multiple types of brain cells. Although the previous studies reviewed in this article demonstrate that deregulations of mTOR signaling in NSCs are responsible for a number of brain developmental disorders and pediatric brain tumors, it still remains a question whether mTOR signaling is also altered in developmental brain disorders and pediatric brain tumors without the genetic factors listed in this article (TSC, NF1 and