Advertisement

Mechanisms of self-renewal in human embryonic stem cells

  • Rebecca Stewart
    Correspondence
    Corresponding author: Tel.: +44 191 2418619; fax: +44 191 2418666.
    Affiliations
    Centre for Stem Cell Biology and Developmental Genetics, Institute of Human Genetics, Newcastle University, International Centre for Life, Central Parkway, Newcastle-Upon-Tyne NE1 3BZ, UK
    Search for articles by this author
  • Author Footnotes
    1 Tel.: +44 191 2418643; fax: +44 191 2418666.
    Miodrag Stojkovic
    Footnotes
    1 Tel.: +44 191 2418643; fax: +44 191 2418666.
    Affiliations
    Centre for Stem Cell Biology and Developmental Genetics, Institute of Human Genetics, Newcastle University, International Centre for Life, Central Parkway, Newcastle-Upon-Tyne NE1 3BZ, UK
    Search for articles by this author
  • Author Footnotes
    2 Tel.: +44 191 2418688; fax: +44 191 2418666.
    Majlinda Lako
    Footnotes
    2 Tel.: +44 191 2418688; fax: +44 191 2418666.
    Affiliations
    Centre for Stem Cell Biology and Developmental Genetics, Institute of Human Genetics, Newcastle University, International Centre for Life, Central Parkway, Newcastle-Upon-Tyne NE1 3BZ, UK
    Search for articles by this author
  • Author Footnotes
    1 Tel.: +44 191 2418643; fax: +44 191 2418666.
    2 Tel.: +44 191 2418688; fax: +44 191 2418666.

      Abstract

      Embryonic stem cells (ESCs) are the pluripotent cell population derived from the inner cell mass of pre-implantation embryos and are characterised by prolonged self-renewal and the potential to differentiate into cells representing all three germ layers both in vitro and in vivo. Preservation of the undifferentiated status of the ESC population requires the maintenance of self-renewal whilst inhibiting differentiation and regulating senescence and apoptosis. In this review, we discuss the intrinsic and extrinsic factors associated with self-renewal process, together with possible signalling pathway interactions and mechanisms of regulation.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Thomson J.A.
        • Itskovitz-Eldor J.
        • Shapiro S.S.
        • Waknitz M.A.
        • Swiergiel J.J.
        • Marshall V.S.
        • et al.
        Embryonic stem cell lines derived from human blastocysts.
        Science. 1998; 282: 1145-1147
        • Reubinoff B.E.
        • Pera M.F.
        • Fong C.Y.
        • Trounson A.
        • Bongso A.
        Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro.
        Nat Biotechnol. 2000; 18: 399-404
        • Stojkovic M.
        • Lako M.
        • Stojkovic P.
        • Stewart R.
        • Przyborski S.
        • Armstrong L.
        • et al.
        Derivation of human embryonic stem cells from day-8 blastocysts recovered after three-step in vitro culture.
        Stem Cells. 2004; 22: 790-797
        • Strelchenko N.
        • Verlinsky O.
        • Kukharenko V.
        • Verlinsky Y.
        Morula-derived human embryonic stem cells.
        Reprod Biomed. 2004; 9 ([online]): 623-629
        • Martin G.R.
        Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells.
        Proc Natl Acad Sci USA. 1981; 78: 7634-7638
        • Evans M.J.
        • Kaufman M.H.
        Establishment in culture of pluripotential cells from mouse embryos.
        Nature. 1981; 292: 154-156
        • Amit M.
        • Itskovitz-Eldor J.
        Derivation and spontaneous differentiation of human embryonic stem cells.
        J Anat. 2002; 200: 225-232
        • Xie C.Q.
        • Lin G.
        • Yuan D.
        • Wang J.
        • Liu T.C.
        • Lu G.X.
        Proliferative feeder cells support prolonged expansion of human embryonic stem cells.
        Cell Biol Int. 2005;
        • Xu C.
        • Inokuma M.S.
        • Denham J.
        • Golds K.
        • Kundu P.
        • Gold J.D.
        • et al.
        Feeder-free growth of undifferentiated human embryonic stem cells.
        Nat Biotechnol. 2001; 19: 971-974
        • Wang G.
        • Zhang H.
        • Zhao Y.
        • Li J.
        • Cai J.
        • Wang P.
        • et al.
        Noggin and bFGF cooperate to maintain the pluripotency of human embryonic stem cells in the absence of feeder layers.
        Biochem Biophys Res Commun. 2005; 330: 934-942
        • Amit M.
        • Shariki C.
        • Margulets V.
        • Itskovitz-Eldor J.
        Feeder layer- and serum-free culture of human embryonic stem cells.
        Biol Reprod. 2004; 70: 837-845
        • Stojkovic P.
        • Lako M.
        • Stewart R.
        • Przyborski S.
        • Armstrong L.
        • Evans J.
        • et al.
        An autogeneic feeder cell system that efficiently supports growth of undifferentiated human embryonic stem cells.
        Stem Cells. 2005; 23: 306-314
        • Stojkovic P.
        • Lako M.
        • Przyborski S.
        • Stewart R.
        • Armstrong L.
        • Evans J.
        • et al.
        Human-serum matrix supports undifferentiated growth of human embryonic stem cells.
        Stem Cells. 2005;
        • Henderson J.K.
        • Draper J.S.
        • Baillie H.S.
        • Fishel S.
        • Thomson J.A.
        • Moore H.
        • et al.
        Preimplantation human embryos and embryonic stem cells show comparable expression of stage-specific embryonic antigens.
        Stem Cells. 2002; 20: 329-337
        • Draper J.S.
        • Pigott C.
        • Thomson J.A.
        • Andrews P.W.
        Surface antigens of human embryonic stem cells: changes upon differentiation in culture.
        J Anat. 2002; 200: 249-258
        • Shevinsky L.H.
        • Knowles B.B.
        • Damjanov I.
        • Solter D.
        Monoclonal antibody to murine embryos defines a stage-specific embryonic antigen expressed on mouse embryos and human teratocarcinoma cells.
        Cell. 1982; 30: 697-705
        • Solter D.
        • Knowles B.B.
        Monoclonal antibody defining a stage-specific mouse embryonic antigen (SSEA-1).
        Proc Natl Acad Sci USA. 1978; 75: 5565-5569
        • Kannagi R.
        • Cochran N.A.
        • Ishigami F.
        • Hakomori S.
        • Andrews P.W.
        • Knowles B.B.
        • et al.
        Stage-specific embryonic antigens (SSEA-3 and -4) are epitopes of a unique globo-series ganglioside isolated from human teratocarcinoma cells.
        Embo J. 1983; 2: 2355-2361
        • Berstine E.G.
        • Hooper M.L.
        • Grandchamp S.
        • Ephrussi B.
        Alkaline phosphatase activity in mouse teratoma.
        Proc Natl Acad Sci USA. 1973; 70: 3899-3903
        • Andrews P.W.
        • Meyer L.J.
        • Bednarz K.L.
        • Harris H.
        Two monoclonal antibodies recognizing determinants on human embryonal carcinoma cells react specifically with the liver isozyme of human alkaline phosphatase.
        Hybridoma. 1984; 3: 33-39
        • Chambers I.
        • Colby D.
        • Robertson M.
        • Nichols J.
        • Lee S.
        • Tweedie S.
        • et al.
        Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells.
        Cell. 2003; 113: 643-655
        • Mitsui K.
        • Tokuzawa Y.
        • Itoh H.
        • Segawa K.
        • Murakami M.
        • Takahashi K.
        • et al.
        The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells.
        Cell. 2003; 113: 631-642
        • Palmieri S.L.
        • Peter W.
        • Hess H.
        • Scholer H.R.
        Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation.
        Dev Biol. 1994; 166: 259-267
        • Bhattacharya B.
        • Miura T.
        • Brandenberger R.
        • Mejido J.
        • Luo Y.
        • Yang A.X.
        • et al.
        Gene expression in human embryonic stem cell lines: unique molecular signature.
        Blood. 2004; 103: 2956-2964
        • Arceci R.J.
        • King A.A.
        • Simon M.C.
        • Orkin S.H.
        • Wilson D.B.
        Mouse GATA-4: a retinoic acid-inducible GATA-binding transcription factor expressed in endodermally derived tissues and heart.
        Mol Cell Biol. 1993; 13: 2235-2246
        • Koutsourakis M.
        • Langeveld A.
        • Patient R.
        • Beddington R.
        • Grosveld F.
        The transcription factor GATA6 is essential for early extraembryonic development.
        Development. 1999; 126: 723-732
      1. Hyslop LA, Stojkovic M, Armstrong L, Walter T, Stojkovic P, Przyborski S, et al. Downregulation of NANOG induces differentiation of Human Embryonic Stem Cells to Extraembryonic Lineages. Stem Cells Express, published online June 27, 2005. doi:10.1634/stemcells.2005-0080.

        • Beck F.
        • Erler T.
        • Russell A.
        • James R.
        Expression of Cdx-2 in the mouse embryo and placenta: possible role in patterning of the extra-embryonic membranes.
        Dev Dyn. 1995; 204: 219-227
        • Rossant J.
        Lineage development and polar asymmetries in the peri-implantation mouse blastocyst.
        Semin Cell Dev Biol. 2004; 15: 573-581
        • Kuroda T.
        • Tada M.
        • Kubota H.
        • Kimura H.
        • Hatano S.Y.
        • Suemori H.
        • et al.
        Octamer and Sox elements are required for transcriptional cis regulation of Nanog gene expression.
        Mol Cell Biol. 2005; 25: 2475-2485
        • Rodda D.J.
        • Chew J.L.
        • Lim L.H.
        • Loh Y.H.
        • Wang B.
        • Ng H.H.
        • et al.
        Transcriptional regulation of nanog by OCT4 and SOX2.
        J Biol Chem. 2005;
        • Scholer H.R.
        Octamania: the POU factors in murine development.
        Trends Genet. 1991; 7: 323-329
        • Pesce M.
        • Scholer H.R.
        Oct-4: gatekeeper in the beginnings of mammalian development.
        Stem Cells. 2001; 19: 271-278
        • Stevanovic M.
        • Zuffardi O.
        • Collignon J.
        • Lovell-Badge R.
        • Goodfellow P.
        The cDNA sequence and chromosomal location of the human SOX2 gene.
        Mamm Genome. 1994; 5: 640-642
        • Pan G.J.
        • Chang Z.Y.
        • Scholer H.R.
        • Pei D.
        Stem cell pluripotency and transcription factor Oct4.
        Cell Res. 2002; 12: 321-329
        • Niwa H.
        Molecular mechanism to maintain stem cell renewal of ES cells.
        Cell Struct Funct. 2001; 26: 137-148
        • Nichols J.
        • Zevnik B.
        • Anastassiadis K.
        • Niwa H.
        • Klewe-Nebenius D.
        • Chambers I.
        • et al.
        Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4.
        Cell. 1998; 95: 379-391
        • Niwa H.
        • Miyazaki J.
        • Smith A.G.
        Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells.
        Nat Genet. 2000; 24: 372-376
        • Avilion A.A.
        • Nicolis S.K.
        • Pevny L.H.
        • Perez L.
        • Vivian N.
        • Lovell-Badge R.
        Multipotent cell lineages in early mouse development depend on SOX2 function.
        Genes Dev. 2003; 17: 126-140
        • Ambrosetti D.C.
        • Scholer H.R.
        • Dailey L.
        • Basilico C.
        Modulation of the activity of multiple transcriptional activation domains by the DNA binding domains mediates the synergistic action of Sox2 and Oct-3 on the fibroblast growth factor-4 enhancer.
        J Biol Chem. 2000; 275: 23387-23397
        • Yuan H.
        • Corbi N.
        • Basilico C.
        • Dailey L.
        Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3.
        Genes Dev. 1995; 9: 2635-2645
        • Nishimoto M.
        • Fukushima A.
        • Okuda A.
        • Muramatsu M.
        The gene for the embryonic stem cell coactivator UTF1 carries a regulatory element which selectively interacts with a complex composed of Oct-3/4 and Sox-2.
        Mol Cell Biol. 1999; 19: 5453-5465
        • Tokuzawa Y.
        • Kaiho E.
        • Maruyama M.
        • Takahashi K.
        • Mitsui K.
        • Maeda M.
        • et al.
        Fbx15 is a novel target of Oct3/4 but is dispensable for embryonic stem cell self-renewal and mouse development.
        Mol Cell Biol. 2003; 23: 2699-2708
        • Robson P.
        The maturing of the human embryonic stem cell transcriptome profile.
        Trends Biotechnol. 2004; 22: 609-612
        • Richards M.
        • Tan S.P.
        • Tan J.H.
        • Chan W.K.
        • Bongso A.
        The transcriptome profile of human embryonic stem cells as defined by SAGE.
        Stem Cells. 2004; 22: 51-64
        • Brandenberger R.
        • Khrebtukova I.
        • Thies R.S.
        • Miura T.
        • Jingli C.
        • Puri R.
        • et al.
        MPSS profiling of human embryonic stem cells.
        BMC Dev Biol. 2004; 4: 10
        • Okano M.
        • Xie S.
        • Li E.
        Cloning and characterization of a family of novel mammalian DNA (cytosine-5) methyltransferases.
        Nat Genet. 1998; 19: 219-220
        • Blackburn E.H.
        Switching and signaling at the telomere.
        Cell. 2001; 106: 661-673
        • Hemann M.T.
        • Greider C.W.
        G-strand overhangs on telomeres in telomerase-deficient mouse cells.
        Nucleic Acids Res. 1999; 27: 3964-3969
        • de Lange T.
        Protection of mammalian telomeres.
        Oncogene. 2002; 21: 532-540
        • Griffith J.D.
        • Comeau L.
        • Rosenfield S.
        • Stansel R.M.
        • Bianchi A.
        • Moss H.
        • et al.
        Mammalian telomeres end in a large duplex loop.
        Cell. 1999; 97: 503-514
        • Munoz-Jordan J.L.
        • Cross G.A.
        • de Lange T.
        • Griffith J.D.
        t-loops at trypanosome telomeres.
        Embo J. 2001; 20: 579-588
        • Watson J.D.
        Origin of concatemeric T7 DNA.
        Nat New Biol. 1972; 239: 197-201
        • Olovnikov A.M.
        A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon.
        J Theor Biol. 1973; 41: 181-190
        • Harley C.B.
        • Sherwood S.W.
        Telomerase, checkpoints and cancer.
        Cancer Surv. 1997; 29: 263-284
        • Harley C.B.
        Telomere loss: mitotic clock or genetic time bomb?.
        Mutat Res. 1991; 256: 271-282
        • Von Zglinicki T.
        Replicative senescence and the art of counting.
        Exp Gerontol. 2003; 38: 1259-1264
        • Wright W.E.
        • Shay J.W.
        The two-stage mechanism controlling cellular senescence and immortalization.
        Exp Gerontol. 1992; 27: 383-389
        • Maser R.S.
        • DePinho R.A.
        Connecting chromosomes, crisis, and cancer.
        Science. 2002; 297: 565-569
        • Greider C.W.
        • Blackburn E.H.
        Identification of a specific telomere terminal transferase activity in Tetrahymena extracts.
        Cell. 1985; 43: 405-413
        • Weinrich S.L.
        • Pruzan R.
        • Ma L.
        • Ouellette M.
        • Tesmer V.M.
        • Holt S.E.
        • et al.
        Reconstitution of human telomerase with the template RNA component hTR and the catalytic protein subunit hTRT.
        Nat Genet. 1997; 17: 498-502
        • Beattie T.L.
        • Zhou W.
        • Robinson M.O.
        • Harrington L.
        Reconstitution of human telomerase activity in vitro.
        Curr Biol. 1998; 8: 177-180
        • Chang J.T.
        • Chen Y.L.
        • Yang H.T.
        • Chen C.Y.
        • Cheng A.J.
        Differential regulation of telomerase activity by six telomerase subunits.
        Eur J Biochem. 2002; 269: 3442-3450
        • Armstrong L.
        • Lako M.
        • Lincoln J.
        • Cairns P.M.
        • Hole N.
        mTert expression correlates with telomerase activity during the differentiation of murine embryonic stem cells.
        Mech Dev. 2000; 97: 109-116
        • Liu Y.
        • Snow B.E.
        • Hande M.P.
        • Yeung D.
        • Erdmann N.J.
        • Wakeham A.
        • et al.
        The telomerase reverse transcriptase is limiting and necessary for telomerase function in vivo.
        Curr Biol. 2000; 10: 1459-1462
        • Niida H.
        • Matsumoto T.
        • Satoh H.
        • Shiwa M.
        • Tokutake Y.
        • Furuichi Y.
        • et al.
        Severe growth defect in mouse cells lacking the telomerase RNA component.
        Nat Genet. 1998; 19: 203-206
        • Lee M.K.
        • Hande M.P.
        • Sabapathy K.
        Ectopic mTERT expression in mouse embryonic stem cells does not affect differentiation but confers resistance to differentiation- and stress-induced p53-dependent apoptosis.
        J Cell Sci. 2005; 118: 819-829
        • Armstrong L.
        • Saretzki G.
        • Peters H.
        • Wappler I.
        • Evans J.
        • Hole N.
        • et al.
        Overexpression of telomerase confers growth advantage, stress resistance, and enhanced differentiation of ESCs toward the hematopoietic lineage.
        Stem Cells. 2005; 23: 516-529
        • Murnane J.P.
        • Sabatier L.
        • Marder B.A.
        • Morgan W.F.
        Telomere dynamics in an immortal human cell line.
        Embo J. 1994; 13: 4953-4962
        • Bryan T.M.
        • Englezou A.
        • Gupta J.
        • Bacchetti S.
        • Reddel R.R.
        Telomere elongation in immortal human cells without detectable telomerase activity.
        Embo J. 1995; 14: 4240-4248
        • Henson J.D.
        • Neumann A.A.
        • Yeager T.R.
        • Reddel R.R.
        Alternative lengthening of telomeres in mammalian cells.
        Oncogene. 2002; 21: 598-610
        • Neumann A.A.
        • Reddel R.R.
        Telomere maintenance and cancer – look, no telomerase.
        Nat Rev Cancer. 2002; 2: 879-884
        • Desmaze C.
        • Soria J.C.
        • Freulet-Marriere M.A.
        • Mathieu N.
        • Sabatier L.
        Telomere-driven genomic instability in cancer cells.
        Cancer Lett. 2003; 194: 173-182
        • Smith A.G.
        • Hooper M.L.
        Buffalo rat liver cells produce a diffusible activity which inhibits the differentiation of murine embryonal carcinoma and embryonic stem cells.
        Dev Biol. 1987; 121: 1-9
        • Smith A.G.
        • Heath J.K.
        • Donaldson D.D.
        • Wong G.G.
        • Moreau J.
        • Stahl M.
        • et al.
        Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides.
        Nature. 1988; 336: 688-690
        • Williams R.L.
        • Hilton D.J.
        • Pease S.
        • Willson T.A.
        • Stewart C.L.
        • Gearing D.P.
        • et al.
        Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells.
        Nature. 1988; 336: 684-687
        • Niwa H.
        • Burdon T.
        • Chambers I.
        • Smith A.
        Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3.
        Genes Dev. 1998; 12: 2048-2060
        • Burdon T.
        • Stracey C.
        • Chambers I.
        • Nichols J.
        • Smith A.
        Suppression of SHP-2 and ERK signalling promotes self-renewal of mouse embryonic stem cells.
        Dev Biol. 1999; 210: 30-43
        • Xie X.
        • Chan R.J.
        • Yoder M.C.
        Thrombopoietin acts synergistically with LIF to maintain an undifferentiated state of embryonic stem cells homozygous for a Shp-2 deletion mutation.
        FEBS Lett. 2002; 529: 361-364
        • Takahashi A.
        • Takahashi Y.
        • Matsumoto K.
        • Miyata K.
        Synergistic effects of insulin-like growth factor II (IGF-II) with leukemia inhibiting factor (LIF) on establishment of rat pluripotential cell lines.
        J Vet Med Sci. 1995; 57: 553-556
        • Viswanathan S.
        • Benatar T.
        • Mileikovsky M.
        • Lauffenburger D.A.
        • Nagy A.
        • Zandstra P.W.
        Supplementation-dependent differences in the rates of embryonic stem cell self-renewal, differentiation, and apoptosis.
        Biotechnol Bioeng. 2003; 84: 505-517
        • Oka M.
        • Tagoku K.
        • Russell T.L.
        • Nakano Y.
        • Hamazaki T.
        • Meyer E.M.
        • et al.
        CD9 is associated with leukemia inhibitory factor-mediated maintenance of embryonic stem cells.
        Mol Biol Cell. 2002; 13: 1274-1281
        • Ying Q.L.
        • Nichols J.
        • Chambers I.
        • Smith A.
        BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3.
        Cell. 2003; 115: 281-292
        • Berger C.N.
        • Sturm K.S.
        Self renewal of embryonic stem cells in the absence of feeder cells and exogenous leukaemia inhibitory factor.
        Growth Factors. 1997; 14: 145-159
        • Gendall A.R.
        • Dunn A.R.
        • Ernst M.
        Isolation and characterization of a leukemia inhibitory factor-independent embryonic stem cell line.
        Int J Biochem Cell Biol. 1997; 29: 829-840
        • Rao M.
        Conserved and divergent paths that regulate self-renewal in mouse and human embryonic stem cells.
        Dev Biol. 2004; 275: 269-286
        • Kolch W.
        Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions.
        Biochem J. 2000; 351: 289-305
        • Burdon T.
        • Smith A.
        • Savatier P.
        Signalling, cell cycle and pluripotency in embryonic stem cells.
        Trends Cell Biol. 2002; 12: 432-438
        • Paling N.R.
        • Wheadon H.
        • Bone H.K.
        • Welham M.J.
        Regulation of embryonic stem cell self-renewal by phosphoinositide 3-kinase-dependent signaling.
        J Biol Chem. 2004; 279: 48063-48070
        • Burdon T.
        • Chambers I.
        • Stracey C.
        • Niwa H.
        • Smith A.
        Signaling mechanisms regulating self-renewal and differentiation of pluripotent embryonic stem cells.
        Cells Tissues Organs. 1999; 165: 131-143
        • Daheron L.
        • Opitz S.L.
        • Zaehres H.
        • Lensch W.M.
        • Andrews P.W.
        • Itskovitz-Eldor J.
        • et al.
        LIF/STAT3 signaling fails to maintain self-renewal of human embryonic stem cells.
        Stem Cells. 2004; 22: 770-778
        • Humphrey R.K.
        • Beattie G.M.
        • Lopez A.D.
        • Bucay N.
        • King C.C.
        • Firpo M.T.
        • et al.
        Maintenance of pluripotency in human embryonic stem cells is STAT3 independent.
        Stem Cells. 2004; 22: 522-530
        • Mantalenakis S.J.
        • Ketchel M.M.
        Frequency and extent of delayed implantation in lactating rats and mice.
        J Reprod Fertil. 1966; 12: 391-394
        • Yoshinaga K.
        • Adams C.E.
        Delayed implantation in the spayed, progesterone treated adult mouse.
        J Reprod Fertil. 1966; 12: 593-595
        • Nichols J.
        • Chambers I.
        • Taga T.
        • Smith A.
        Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines.
        Development. 2001; 128: 2333-2339
        • James D.
        • Levine A.J.
        • Besser D.
        • Hemmati-Brivanlou A.
        TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells.
        Development. 2005; 132: 1273-1282
        • Miyazono K.
        • ten Dijke P.
        • Heldin C.H.
        TGF-beta signaling by Smad proteins.
        Adv Immunol. 2000; 75: 115-157
        • Laping N.J.
        • Grygielko E.
        • Mathur A.
        • Butter S.
        • Bomberger J.
        • Tweed C.
        • et al.
        Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542.
        Mol Pharmacol. 2002; 62: 58-64
        • Schier A.F.
        Nodal signaling in vertebrate development.
        Annu Rev Cell Dev Biol. 2003; 19: 589-621
        • Brennan J.
        • Lu C.C.
        • Norris D.P.
        • Rodriguez T.A.
        • Beddington R.S.
        • Robertson E.J.
        Nodal signalling in the epiblast patterns the early mouse embryo.
        Nature. 2001; 411: 965-969
        • Erter C.E.
        • Solnica-Krezel L.
        • Wright C.V.
        Zebrafish nodal-related 2 encodes an early mesendodermal inducer signaling from the extraembryonic yolk syncytial layer.
        Dev Biol. 1998; 204: 361-372
        • Bertocchini F.
        • Stern C.D.
        The hypoblast of the chick embryo positions the primitive streak by antagonizing nodal signaling.
        Dev Cell. 2002; 3: 735-744
        • Jones C.M.
        • Kuehn M.R.
        • Hogan B.L.
        • Smith J.C.
        • Wright C.V.
        Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation.
        Development. 1995; 121: 3651-3662
        • Perea-Gomez A.
        • Vella F.D.
        • Shawlot W.
        • Oulad-Abdelghani M.
        • Chazaud C.
        • Meno C.
        • et al.
        Nodal antagonists in the anterior visceral endoderm prevent the formation of multiple primitive streaks.
        Dev Cell. 2002; 3: 745-756
        • Conlon F.L.
        • Lyons K.M.
        • Takaesu N.
        • Barth K.S.
        • Kispert A.
        • Herrmann B.
        • et al.
        A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse.
        Development. 1994; 120: 1919-1928
        • Robertson E.J.
        • Norris D.P.
        • Brennan J.
        • Bikoff E.K.
        Control of early anterior-posterior patterning in the mouse embryo by TGF-beta signalling.
        Philos Trans R Soc Lond B Biol Sci. 2003; 358 ([discussion 7]): 1351-1357
        • Vallier L.
        • Reynolds D.
        • Pedersen R.A.
        Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway.
        Dev Biol. 2004; 275: 403-421
        • Besser D.
        Expression of nodal, lefty-a, and lefty-B in undifferentiated human embryonic stem cells requires activation of Smad2/3.
        J Biol Chem. 2004; 279: 45076-45084
        • Gu Z.
        • Reynolds E.M.
        • Song J.
        • Lei H.
        • Feijen A.
        • Yu L.
        • et al.
        The type I serine/threonine kinase receptor ActRIA (ALK2) is required for gastrulation of the mouse embryo.
        Development. 1999; 126: 2551-2561
        • Oh S.P.
        • Li E.
        The signaling pathway mediated by the type IIB activin receptor controls axial patterning and lateral asymmetry in the mouse.
        Genes Dev. 1997; 11: 1812-1826
        • Song J.
        • Oh S.P.
        • Schrewe H.
        • Nomura M.
        • Lei H.
        • Okano M.
        • et al.
        The type II activin receptors are essential for egg cylinder growth, gastrulation, and rostral head development in mice.
        Dev Biol. 1999; 213: 157-169
        • Gritsman K.
        • Zhang J.
        • Cheng S.
        • Heckscher E.
        • Talbot W.S.
        • Schier A.F.
        The EGF-CFC protein one-eyed pinhead is essential for nodal signaling.
        Cell. 1999; 97: 121-132
        • Beck S.
        • Le Good J.A.
        • Guzman M.
        • Ben Haim N.
        • Roy K.
        • Beermann F.
        • et al.
        Extraembryonic proteases regulate Nodal signalling during gastrulation.
        Nat Cell Biol. 2002; 4: 981-985
        • Vale W.
        • Rivier J.
        • Vaughan J.
        • McClintock R.
        • Corrigan A.
        • Woo W.
        • et al.
        Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid.
        Nature. 1986; 321: 776-779
        • Ling N.
        • Ying S.Y.
        • Ueno N.
        • Shimasaki S.
        • Esch F.
        • Hotta M.
        • et al.
        Pituitary FSH is released by a heterodimer of the beta-subunits from the two forms of inhibin.
        Nature. 1986; 321: 779-782
        • Vale W.
        • Rivier C.
        • Hsueh A.
        • Campen C.
        • Meunier H.
        • Bicsak T.
        • et al.
        Chemical and biological characterization of the inhibin family of protein hormones.
        Recent Prog Horm Res. 1988; 44: 1-34
        • Kingsley D.M.
        The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms.
        Genes Dev. 1994; 8: 133-146
        • Levenberg S.
        • Huang N.F.
        • Lavik E.
        • Rogers A.B.
        • Itskovitz-Eldor J.
        • Langer R.
        Differentiation of human embryonic stem cells on three-dimensional polymer scaffolds.
        Proc Natl Acad Sci USA. 2003; 100: 12741-12746
        • Hashimoto M.
        • Kondo S.
        • Sakurai T.
        • Etoh Y.
        • Shibai H.
        • Muramatsu M.
        Activin/EDF as an inhibitor of neural differentiation.
        Biochem Biophys Res Commun. 1990; 173: 193-200
        • Johansson B.M.
        • Wiles M.V.
        Evidence for involvement of activin A and bone morphogenetic protein 4 in mammalian mesoderm and hematopoietic development.
        Mol Cell Biol. 1995; 15: 141-151
        • Demeterco C.
        • Beattie G.M.
        • Dib S.A.
        • Lopez A.D.
        • Hayek A.
        A role for activin A and betacellulin in human fetal pancreatic cell differentiation and growth.
        J Clin Endocrinol Metab. 2000; 85: 3892-3897
        • Kubo A.
        • Shinozaki K.
        • Shannon J.M.
        • Kouskoff V.
        • Kennedy M.
        • Woo S.
        • et al.
        Development of definitive endoderm from embryonic stem cells in culture.
        Development. 2004; 131: 1651-1662
        • Beattie G.M.
        • Lopez A.D.
        • Bucay N.
        • Hinton A.
        • Firpo M.T.
        • King C.C.
        • et al.
        Activin A maintains pluripotency of human embryonic stem cells in the absence of feeder layers.
        Stem Cells. 2005; 23: 489-495
        • Zhang J.
        • Li L.
        BMP signaling and stem cell regulation.
        Dev Biol. 2005;
        • Massague J.
        TGFbeta signaling: receptors, transducers, and Mad proteins.
        Cell. 1996; 85: 947-950
        • Massague J.
        • Wotton D.
        Transcriptional control by the TGF-beta/Smad signaling system.
        Embo J. 2000; 19: 1745-1754
        • Nakashima K.
        • Takizawa T.
        • Ochiai W.
        • Yanagisawa M.
        • Hisatsune T.
        • Nakafuku M.
        • et al.
        BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis.
        Proc Natl Acad Sci USA. 2001; 98: 5868-5873
        • Ruzinova M.B.
        • Benezra R.
        Id proteins in development, cell cycle and cancer.
        Trends Cell Biol. 2003; 13: 410-418
        • Norton J.D.
        ID helix-loop-helix proteins in cell growth, differentiation and tumorigenesis.
        J Cell Sci. 2000; 113: 3897-3905
        • Qi X.
        • Li T.G.
        • Hao J.
        • Hu J.
        • Wang J.
        • Simmons H.
        • et al.
        BMP4 supports self-renewal of embryonic stem cells by inhibiting mitogen-activated protein kinase pathways.
        Proc Natl Acad Sci USA. 2004; 101: 6027-6032
        • Xu R.H.
        • Chen X.
        • Li D.S.
        • Li R.
        • Addicks G.C.
        • Glennon C.
        • et al.
        BMP4 initiates human embryonic stem cell differentiation to trophoblast.
        Nat Biotechnol. 2002; 20: 1261-1264
        • Basilico C.
        • Moscatelli D.
        The FGF family of growth factors and oncogenes.
        Adv Cancer Res. 1992; 59: 115-165
        • Boilly B.
        • Vercoutter-Edouart A.S.
        • Hondermarck H.
        • Nurcombe V.
        • Le Bourhis X.
        FGF signals for cell proliferation and migration through different pathways.
        Cytokine Growth Factor Rev. 2000; 11: 295-302
        • Hondermarck H.
        • McLaughlin C.S.
        • Patterson S.D.
        • Bradshaw R.A.
        Early changes in protein synthesis induced by basic fibroblast growth factor, nerve growth factor, and epidermal growth factor in PC12 pheochromocytoma cells.
        Proc Natl Acad Sci USA. 1994; 91: 9377-9381
        • Minina E.
        • Kreschel C.
        • Naski M.C.
        • Ornitz D.M.
        • Vortkamp A.
        Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation.
        Dev Cell. 2002; 3: 439-449
        • Dailey L.
        • Laplantine E.
        • Priore R.
        • Basilico C.
        A network of transcriptional and signaling events is activated by FGF to induce chondrocyte growth arrest and differentiation.
        J Cell Biol. 2003; 161: 1053-1066
        • Sahni M.
        • Ambrosetti D.C.
        • Mansukhani A.
        • Gertner R.
        • Levy D.
        • Basilico C.
        FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway.
        Genes Dev. 1999; 13: 1361-1366
        • Kim S.J.
        • Cheon S.H.
        • Yoo S.J.
        • Kwon J.
        • Park J.H.
        • Kim C.G.
        • et al.
        Contribution of the PI3K/Akt/PKB signal pathway to maintenance of self-renewal in human embryonic stem cells.
        FEBS Lett. 2005; 579: 534-540
        • Xu R.H.
        • Peck R.M.
        • Li D.S.
        • Feng X.
        • Ludwig T.
        • Thomson J.A.
        Basic FGF and suppression of BMP signaling sustain undifferentiated proliferation of human ES cells.
        Nat Methods. 2005; 2: 185-190
        • Johnson D.E.
        • Williams L.T.
        Structural and functional diversity in the FGF receptor multigene family.
        Adv Cancer Res. 1993; 60: 1-41
        • Schlessinger J.
        Cell signaling by receptor tyrosine kinases.
        Cell. 2000; 103: 211-225
        • Dailey L.
        • Ambrosetti D.
        • Mansukhani A.
        • Basilico C.
        Mechanisms underlying differential responses to FGF signaling.
        Cytokine Growth Factor Rev. 2005; 16: 233-247
        • Nakayama K.
        • Tamura Y.
        • Suzawa M.
        • Harada S.
        • Fukumoto S.
        • Kato M.
        • et al.
        Receptor tyrosine kinases inhibit bone morphogenetic protein-Smad responsive promoter activity and differentiation of murine MC3T3-E1 osteoblast-like cells.
        J Bone Miner Res. 2003; 18: 827-835
        • Aubin J.
        • Davy A.
        • Soriano P.
        In vivo convergence of BMP and MAPK signaling pathways: impact of differential Smad1 phosphorylation on development and homeostasis.
        Genes Dev. 2004; 18: 1482-1494
        • Williams M.R.
        • Arthur J.S.
        • Balendran A.
        • van der Kaay J.
        • Poli V.
        • Cohen P.
        • et al.
        The role of 3-phosphoinositide-dependent protein kinase 1 in activating AGC kinases defined in embryonic stem cells.
        Curr Biol. 2000; 10: 439-448
        • Waite K.A.
        • Eng C.
        From developmental disorder to heritable cancer: it’s all in the BMP/TGF-beta family.
        Nat Rev Genet. 2003; 4: 763-773
        • Waite K.A.
        • Eng C.
        BMP2 exposure results in decreased PTEN protein degradation and increased PTEN levels.
        Hum Mol Genet. 2003; 12: 679-684
        • Stambolic V.
        • Mak T.W.
        • Woodgett J.R.
        Modulation of cellular apoptotic potential: contributions to oncogenesis.
        Oncogene. 1999; 18: 6094-6103
        • Bienz M.
        • Clevers H.
        Linking colorectal cancer to Wnt signaling.
        Cell. 2000; 103: 311-320
        • Aberle H.
        • Bauer A.
        • Stappert J.
        • Kispert A.
        • Kemler R.
        beta-catenin is a target for the ubiquitin-proteasome pathway.
        Embo J. 1997; 16: 3797-3804
        • Barker N.
        • Clevers H.
        Catenins, Wnt signaling and cancer.
        Bioessays. 2000; 22: 961-965
        • Reya T.
        • Clevers H.
        Wnt signalling in stem cells and cancer.
        Nature. 2005; 434: 843-850
        • Bienz M.
        • Clevers H.
        Armadillo/beta-catenin signals in the nucleus–proof beyond a reasonable doubt?.
        Nat Cell Biol. 2003; 5: 179-182
        • Batlle E.
        • Henderson J.T.
        • Beghtel H.
        • van den Born M.M.
        • Sancho E.
        • Huls G.
        • et al.
        Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB.
        Cell. 2002; 111: 251-263
        • van de Wetering M.
        • Sancho E.
        • Verweij C.
        • de Lau W.
        • Oving I.
        • Hurlstone A.
        • et al.
        The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells.
        Cell. 2002; 111: 241-250
        • Huelsken J.
        • Vogel R.
        • Erdmann B.
        • Cotsarelis G.
        • Birchmeier W.
        beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin.
        Cell. 2001; 105: 533-545
        • Alonso L.
        • Fuchs E.
        Stem cells in the skin: waste not, Wnt not.
        Genes Dev. 2003; 17: 1189-1200
        • Sato N.
        • Meijer L.
        • Skaltsounis L.
        • Greengard P.
        • Brivanlou A.H.
        Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor.
        Nat Med. 2004; 10: 55-63
        • Meijer L.
        • Skaltsounis A.L.
        • Magiatis P.
        • Polychronopoulos P.
        • Knockaert M.
        • Leost M.
        • et al.
        GSK-3-selective inhibitors derived from Tyrian purple indirubins.
        Chem Biol. 2003; 10: 1255-1266
        • Naito A.T.
        • Akazawa H.
        • Takano H.
        • Minamino T.
        • Nagai T.
        • Aburatani H.
        • et al.
        Phosphatidylinositol 3-Kinase-Akt Pathway Plays a Critical Role in Early Cardiomyogenesis by Regulating Canonical Wnt Signaling.
        Circ Res. 2005;
        • Tian Q.
        • He X.C.
        • Hood L.
        • Li L.
        Bridging the BMP and Wnt pathways by PI3 kinase/Akt and 14-3-3zeta.
        Cell Cycle. 2005; 4: 215-216
        • Sharma M.
        • Chuang W.W.
        • Sun Z.
        Phosphatidylinositol3-kinase/Akt stimulates androgen pathway through GSK 3beta inhibition and nuclear beta-catenin accumulation.
        J Biol Chem. 2002; 277: 30935-30941
        • Tada T.
        • Tada M.
        Toti-/pluripotential stem cells and epigenetic modifications.
        Cell Struct Funct. 2001; 26: 149-160
        • Geiman T.M.
        • Robertson K.D.
        Chromatin remodeling, histone modifications, and DNA methylation-how does it all fit together?.
        J Cell Biochem. 2002; 87: 117-125
        • Hattori N.
        • Nishino K.
        • Ko Y.G.
        • Hattori N.
        • Ohgane J.
        • Tanaka S.
        • et al.
        Epigenetic control of mouse Oct-4 gene expression in embryonic stem cells and trophoblast stem cells.
        J Biol Chem. 2004; 279: 17063-17069
        • Nan X.
        • Ng H.H.
        • Johnson C.A.
        • Laherty C.D.
        • Turner B.M.
        • Eisenman R.N.
        • et al.
        Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.
        Nature. 1998; 393: 386-389
        • Jones P.L.
        • Veenstra G.J.
        • Wade P.A.
        • Vermaak D.
        • Kass S.U.
        • Landsberger N.
        • et al.
        Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription.
        Nat Genet. 1998; 19: 187-191
        • Yoshida M.
        • Horinouchi S.
        • Beppu T.
        Trichostatin A and trapoxin: novel chemical probes for the role of histone acetylation in chromatin structure and function.
        Bioessays. 1995; 17: 423-430
        • Tsuji-Takayama K.
        • Inoue T.
        • Ijiri Y.
        • Otani T.
        • Motoda R.
        • Nakamura S.
        • et al.
        Demethylating agent, 5-azacytidine, reverses differentiation of embryonic stem cells.
        Biochem Biophys Res Commun. 2004; 323: 86-90
        • Jacobs J.J.
        • van Lohuizen M.
        Polycomb repression: from cellular memory to cellular proliferation and cancer.
        Biochim Biophys Acta. 2002; 1602: 151-161
        • Valk-Lingbeek M.E.
        • Bruggeman S.W.
        • van Lohuizen M.
        Stem cells and cancer; the polycomb connection.
        Cell. 2004; 118: 409-418
        • Schumacher A.
        • Lichtarge O.
        • Schwartz S.
        • Magnuson T.
        The murine Polycomb-group gene eed and its human orthologue: functional implications of evolutionary conservation.
        Genomics. 1998; 54: 79-88
        • Voncken J.W.
        • Roelen B.A.
        • Roefs M.
        • de Vries S.
        • Verhoeven E.
        • Marino S.
        • et al.
        Rnf2 (Ring1b) deficiency causes gastrulation arrest and cell cycle inhibition.
        Proc Natl Acad Sci USA. 2003; 100: 2468-2473
        • O’Carroll D.
        • Erhardt S.
        • Pagani M.
        • Barton S.C.
        • Surani M.A.
        • Jenuwein T.
        The polycomb-group gene Ezh2 is required for early mouse development.
        Mol Cell Biol. 2001; 21: 4330-4336
        • Hitoshi S.
        • Alexson T.
        • Tropepe V.
        • Donoviel D.
        • Elia A.J.
        • Nye J.S.
        • et al.
        Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells.
        Genes Dev. 2002; 16: 846-858
        • Machold R.
        • Hayashi S.
        • Rutlin M.
        • Muzumdar M.D.
        • Nery S.
        • Corbin J.G.
        • et al.
        Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches.
        Neuron. 2003; 39: 937-950
        • Lai K.
        • Kaspar B.K.
        • Gage F.H.
        • Schaffer D.V.
        Sonic hedgehog regulates adult neural progenitor proliferation in vitro and in vivo.
        Nat Neurosci. 2003; 6: 21-27
        • Wechsler-Reya R.
        • Scott M.P.
        The developmental biology of brain tumors.
        Annu Rev Neurosci. 2001; 24: 385-428
        • Gailani M.R.
        • Bale A.E.
        Acquired and inherited basal cell carcinomas and the patched gene.
        Adv Dermatol. 1999; 14 ([discussion 84]): 261-283
        • Ellisen L.W.
        • Bird J.
        • West D.C.
        • Soreng A.L.
        • Reynolds T.C.
        • Smith S.D.
        • et al.
        TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.
        Cell. 1991; 66: 649-661
        • Polakis P.
        Wnt signaling and cancer.
        Genes Dev. 2000; 14: 1837-1851
        • Chan E.F.
        • Gat U.
        • McNiff J.M.
        • Fuchs E.
        A common human skin tumour is caused by activating mutations in beta-catenin.
        Nat Genet. 1999; 21: 410-413
        • Li P.
        • Nicosia S.V.
        • Bai W.
        Antagonism between PTEN/MMAC1/TEP-1 and androgen receptor in growth and apoptosis of prostatic cancer cells.
        J Biol Chem. 2001; 276: 20444-20450
        • Hiyama E.
        • Hiyama K.
        Clinical utility of telomerase in cancer.
        Oncogene. 2002; 21: 643-649
        • Dong C.K.
        • Masutomi K.
        • Hahn W.C.
        Telomerase: regulation, function and transformation.
        Crit Rev Oncol Hematol. 2005; 54: 85-93
        • Kim N.W.
        • Piatyszek M.A.
        • Prowse K.R.
        • Harley C.B.
        • West M.D.
        • Ho P.L.
        • et al.
        Specific association of human telomerase activity with immortal cells and cancer.
        Science. 1994; 266: 2011-2015
        • Hahn W.C.
        Role of telomeres and telomerase in the pathogenesis of human cancer.
        J Clin Oncol. 2003; 21: 2034-2043
        • Hahn W.C.
        • Stewart S.A.
        • Brooks M.W.
        • York S.G.
        • Eaton E.
        • Kurachi A.
        • et al.
        Inhibition of telomerase limits the growth of human cancer cells.
        Nat Med. 1999; 5: 1164-1170
        • Herbert B.
        • Pitts A.E.
        • Baker S.I.
        • Hamilton S.E.
        • Wright W.E.
        • Shay J.W.
        • et al.
        Inhibition of human telomerase in immortal human cells leads to progressive telomere shortening and cell death.
        Proc Natl Acad Sci USA. 1999; 96: 14276-14281
        • Zhang X.
        • Mar V.
        • Zhou W.
        • Harrington L.
        • Robinson M.O.
        Telomere shortening and apoptosis in telomerase-inhibited human tumor cells.
        Genes Dev. 1999; 13: 2388-2399
        • Janknecht R.
        On the road to immortality: hTERT upregulation in cancer cells.
        FEBS Lett. 2004; 564: 9-13
        • Ulaner G.A.
        Telomere maintenance in clinical medicine.
        Am J Med. 2004; 117: 262-269
        • Perrem K.
        • Colgin L.M.
        • Neumann A.A.
        • Yeager T.R.
        • Reddel R.R.
        Coexistence of alternative lengthening of telomeres and telomerase in hTERT-transfected GM847 cells.
        Mol Cell Biol. 2001; 21: 3862-3875
        • Ko L.J.
        • Prives C.
        p53: puzzle and paradigm.
        Genes Dev. 1996; 10: 1054-1072
        • Aladjem M.I.
        • Spike B.T.
        • Rodewald L.W.
        • Hope T.J.
        • Klemm M.
        • Jaenisch R.
        • et al.
        ES cells do not activate p53-dependent stress responses and undergo p53-independent apoptosis in response to DNA damage.
        Curr Biol. 1998; 8: 145-155
        • Lin T.
        • Chao C.
        • Saito S.
        • Mazur S.J.
        • Murphy M.E.
        • Appella E.
        • et al.
        p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression.
        Nat Cell Biol. 2005; 7: 165-171
        • Xu Y.
        A new role for p53 in maintaining genetic stability in embryonic stem cells.
        Cell Cycle. 2005; 4: 363-364
        • Pera M.F.
        • Reubinoff B.
        • Trounson A.
        Human embryonic stem cells.
        J Cell Sci. 2000; 113: 5-10
        • Ginis I.
        • Luo Y.
        • Miura T.
        • Thies S.
        • Brandenberger R.
        • Gerecht-Nir S.
        • et al.
        Differences between human and mouse embryonic stem cells.
        Dev Biol. 2004; 269: 360-380
        • Hosler B.A.
        • LaRosa G.J.
        • Grippo J.F.
        • Gudas L.J.
        Expression of REX-1, a gene containing zinc finger motifs, is rapidly reduced by retinoic acid in F9 teratocarcinoma cells.
        Mol Cell Biol. 1989; 9: 5623-5629
        • Rogers M.B.
        • Hosler B.A.
        • Gudas L.J.
        Specific expression of a retinoic acid-regulated, zinc-finger gene, Rex-1, in preimplantation embryos, trophoblast and spermatocytes.
        Development. 1991; 113: 815-824
        • Hanna L.A.
        • Foreman R.K.
        • Tarasenko I.A.
        • Kessler D.S.
        • Labosky P.A.
        Requirement for Foxd3 in maintaining pluripotent cells of the early mouse embryo.
        Genes Dev. 2002; 16: 2650-2661
        • Guo Y.
        • Costa R.
        • Ramsey H.
        • Starnes T.
        • Vance G.
        • Robertson K.
        • et al.
        The embryonic stem cell transcription factors Oct-4 and FoxD3 interact to regulate endodermal-specific promoter expression.
        Proc Natl Acad Sci USA. 2002; 99: 3663-3667
        • Bierbaum P.
        • MacLean-Hunter S.
        • Ehlert F.
        • Moroy T.
        • Muller R.
        Cloning of embryonal stem cell-specific genes: characterization of the transcriptionally controlled gene esg-1.
        Cell Growth Differ. 1994; 5: 37-46
        • Tanaka T.S.
        • Kunath T.
        • Kimber W.L.
        • Jaradat S.A.
        • Stagg C.A.
        • Usuda M.
        • et al.
        Gene expression profiling of embryo-derived stem cells reveals candidate genes associated with pluripotency and lineage specificity.
        Genome Res. 2002; 12: 1921-1928
        • Niswander L.
        • Martin G.R.
        Fgf-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse.
        Development. 1992; 114: 755-768