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      The differential activation of intracellular signaling pathways confers the permissiveness of embryonic stem cell derivation from different mouse strains

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          Abstract

          The requirement of leukemia inhibitory factor (LIF) for the establishment and maintenance of mouse embryonic stem cells (ESCs) depends on the genetic background of the ESC origin. To reveal the molecular basis of the strain-dependent function of LIF, we compared the activation of the intracellular signaling pathways downstream of LIF in ESCs with different genetic backgrounds. We found that the JAK-Stat3 pathway was dominantly activated in ESCs derived from ‘permissive’ mouse strains (129Sv and C57BL6), whereas the MAP kinase pathway was hyperactivated in ESCs from ‘non-permissive’ strains (NOD, CBA and FVB). Artificial activation of Stat3 supported stable self-renewal of ESCs from non-permissive strains. These data suggest that the difference in the balance between the two intracellular signaling pathways underlies the differential response to LIF.

          Abstract

          Highlighted article: Different mouse strains show distinct JAK-Stat and MAPK activity responses to LIF treatment, accounting for the varying ease of generating stem cells from these lines.

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          Most cited references28

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          Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.

          G Martin (1981)
          This report describes the establishment directly from normal preimplantation mouse embryos of a cell line that forms teratocarcinomas when injected into mice. The pluripotency of these embryonic stem cells was demonstrated conclusively by the observation that subclonal cultures, derived from isolated single cells, can differentiate into a wide variety of cell types. Such embryonic stem cells were isolated from inner cell masses of late blastocysts cultured in medium conditioned by an established teratocarcinoma stem cell line. This suggests that such conditioned medium might contain a growth factor that stimulates the proliferation or inhibits the differentiation of normal pluripotent embryonic cells, or both. This method of obtaining embryonic stem cells makes feasible the isolation of pluripotent cells lines from various types of noninbred embryo, including those carrying mutant genes. The availability of such cell lines should made possible new approaches to the study of early mammalian development.
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            Establishment in culture of pluripotential cells from mouse embryos.

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              Stat3 as an oncogene.

              STATs are latent transcription factors that mediate cytokine- and growth factor-directed transcription. In many human cancers and transformed cell lines, Stat3 is persistently activated, and in cell culture, active Stat3 is either required for transformation, enhances transformation, or blocks apoptosis. We report that substitution of two cysteine residues within the C-terminal loop of the SH2 domain of Stat3 produces a molecule that dimerizes spontaneously, binds to DNA, and activates transcription. The Stat3-C molecule in immortalized fibroblasts causes cellular transformation scored by colony formation in soft agar and tumor formation in nude mice. Thus, the activated Stat3 molecule by itself can mediate cellular transformation and the experiments focus attention on the importance of constitutive Stat3 activation in human tumors.
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                Author and article information

                Journal
                Development
                Development
                DEV
                develop
                Development (Cambridge, England)
                The Company of Biologists
                0950-1991
                1477-9129
                1 February 2015
                1 February 2015
                : 142
                : 3
                : 431-437
                Affiliations
                [1 ]Laboratory for Pluripotent Stem Cell Studies, RIKEN Center for Developmental Biology (CDB) , Minatojima-minamimachi 2-2-3, Chuo-Ku, Kobe 650-0047, Japan
                [2 ]CREST (Core Research for Evolutional Science and Technology), Japan Science Technology Agency , Honcho 4-1-8, Kawaguchi, Saitama 332-0012, Japan
                [3 ]Laboratory for Development and Regenerative Medicine, Kobe University Graduate School of Medicine , 7-5-1 Kusunokicho, Chuo-ku, Kobe 6500017, Japan
                Author notes
                [* ]Author for correspondence ( niwa@ 123456cdb.riken.jp )
                Article
                DEV112375
                10.1242/dev.112375
                4302992
                25564647
                6a4521ff-7b0c-4024-84da-ddac56d4847a
                © 2015. Published by The Company of Biologists Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                History
                : 6 May 2014
                : 5 December 2014
                Categories
                102
                Stem Cells and Regeneration

                Developmental biology
                lif signaling,map kinase,stat3,embryonic stem cell,signal responsiveness
                Developmental biology
                lif signaling, map kinase, stat3, embryonic stem cell, signal responsiveness

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