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      Roles of mTOR Signaling in Brain Development

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          Abstract

          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.

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          Most cited references60

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          Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells.

          Embryonic stem (ES) cells undergo extended proliferation while remaining poised for multilineage differentiation. A unique network of transcription factors may characterize self-renewal and simultaneously suppress differentiation. We applied expression cloning in mouse ES cells to isolate a self-renewal determinant. Nanog is a divergent homeodomain protein that directs propagation of undifferentiated ES cells. Nanog mRNA is present in pluripotent mouse and human cell lines, and absent from differentiated cells. In preimplantation embryos, Nanog is restricted to founder cells from which ES cells can be derived. Endogenous Nanog acts in parallel with cytokine stimulation of Stat3 to drive ES cell self-renewal. Elevated Nanog expression from transgene constructs is sufficient for clonal expansion of ES cells, bypassing Stat3 and maintaining Oct4 levels. Cytokine dependence, multilineage differentiation, and embryo colonization capacity are fully restored upon transgene excision. These findings establish a central role for Nanog in the transcription factor hierarchy that defines ES cell identity.
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            Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4.

            Oct4 is a mammalian POU transcription factor expressed by early embryo cells and germ cells. We report that the activity of Oct4 is essential for the identity of the pluripotential founder cell population in the mammalian embryo. Oct4-deficient embryos develop to the blastocyst stage, but the inner cell mass cells are not pluripotent. Instead, they are restricted to differentiation along the extraembryonic trophoblast lineage. Furthermore, in the absence of a true inner cell mass, trophoblast proliferation is not maintained in Oct4-/- embryos. Expansion of trophoblast precursors is restored, however, by an Oct4 target gene product, fibroblast growth factor-4. Therefore, Oct4 also determines paracrine growth factor signaling from stem cells to the trophectoderm.
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              Growing roles for the mTOR pathway.

              The mammalian TOR (mTOR) pathway is a key regulator of cell growth and proliferation and increasing evidence suggests that its deregulation is associated with human diseases, including cancer and diabetes. The mTOR pathway integrates signals from nutrients, energy status and growth factors to regulate many processes, including autophagy, ribosome biogenesis and metabolism. Recent work identifying two structurally and functionally distinct mTOR-containing multiprotein complexes and TSC1/2, rheb, and AMPK as upstream regulators of mTOR is beginning to reveal how mTOR can sense diverse signals and produce a myriad of responses.
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                Author and article information

                Journal
                Exp Neurobiol
                Exp Neurobiol
                EN
                Experimental Neurobiology
                The Korean Society for Brain and Neural Science
                1226-2560
                2093-8144
                September 2015
                17 September 2015
                : 24
                : 3
                : 177-185
                Affiliations
                Stem Cell Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea.
                Author notes
                To whom correspondence should be addressed. To whom correspondence should be addressed. TEL: 82-42-860-4475, FAX: 82-42-879-8495, daylee@ 123456kribb.re.kr
                Article
                10.5607/en.2015.24.3.177
                4580744
                26412966
                2e74aac1-df08-4589-b8d6-76b78f1976be
                Copyright © Experimental Neurobiology 2015.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 August 2015
                : 02 September 2015
                : 02 September 2015
                Categories
                Review Article

                Neurosciences
                mtor,neurogenesis,gliogenesis,neural stem cell,pediatric brain tumors,brain developmental disorders

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