19 4 2007 8 Chinese Bulletin of Life Sciences Vol. 19, No. 4 Aug., 2007 1004-0374(2007)04-0372-06 510663 (ES ) ES LIF BMP4 Wnt Oct4 Nanog Sox2 FoxD3 ES ES ES Q813 A Molecular mechanisms on embryonic stem cell pluripotency PAN Guangjin, PEI Duanqing* (Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510663, China) Abstract: Derived from early embryo, embryonic stem (ES) cells have potential to self renew indefinitely and develop to any type of cells in human body (pluripotency). Several extrinsic signals such as LIF, BMPs and Wnt can support the self-renewal and pluripotency of embryonic stem (ES) cells through regulating the pluripotent genes. In combination with intrinsic transcription factors such as FoxD3, Nanog, Oct4, these factors form a regulatory network to support or limit each other s expression level, which maintain the properties of ES cells. Key words: embryonic stem cells; self-renewal; differentiation (ES ) (blastocyst) (ICM) [1-3] ICM ES [2-4] ES ES ES ES [5] ES ES ES ES ES 2007-07-10 (1974 ) (1965 ), * E-mail: pei_duanqing@gibh.ac.cn
373 ES ES ES (1)ES (self-renewal) (2) (3) ES ES 1 ES 1.1 LIF STAT3 LIF STAT3 LIF LIF IL-6 LIF gp130 JAKs JAKs LIF gp130 gp130 STATs STAT3 STAT3 STAT3 [6-7] LIF ES LIF ES LIF [8-9] LIF STAT3 ES Niwa [10] ES STAT3 STAT3 LIF ES STAT3 ES [10] 1.2 BMP4 ES ES LIF ES LIF LIF ES LIF ES Ying [11] BMP4 LIF ES LIF BMP4 ES ES ES BMP4 TGF-β SMAD ES BMP4 ID ES ID BMP4 LIF ES Qi [12] BMP4 ES p38mapk [12] 1.3 Wnt ES LIF BMP4 ES ES LIF [13] Wnt ES ES [13-14] GSK Wnt Wnt GSK (Bio) ES GSK Wnt ES ES rex1 oct4 nanog Bio 2 ES ES Oct4 Nanog FoxD3 SoxD3, LIF STAT3 [15-16] ICM Epiblast ES EC( ) 2.1 Oct4 ES Oct4(
374 Oct3) homeodomain POU(Pit-Oct-Unc), AGTCAAAT (octamer motif) Oct4 ES Oct4 Oct4 Oct4 [17-19] Oct4 [20] Oct4 ES Oct4 Niwa [21] Oct4 ES Oct4 Oct4 50% ES (primitive endoderm) Oct4 50% ES (trophoblast) Oct4 ES Oct4 Oct4 352 POU domain N domain C domain POU domain DNA N domain (proline) [22] C domain Brehm [23] Oct4 C domain DNA POU DNA DNA Gal4 Oct4 POU domain Oct4 Oct4 Liu [25-26] Oct4 hcg hcg Oct4 IFN IFN Ets-2 Yamamoto [27] Oct4 Ets-2 Ets-2 IFN Oct4 Oct4 Oct4 [28-32] FGF-4 3' Oct4 Sox2 FGF4 [28-29] UTF1 [32] Oct4 [33-36] Oct4 Oct4 ES 2.2 Nanog ES Nanog ES [37-38] Oct4 Nanog Nanog (murola) ICM Northern blot Nanog [37] Nanog ES (primitive endodern) [38] Nanog (epiblast) ES
375 305 Homeobox Nanog ES LIF-STAT3 Nanog ES LIF ES ES [37-38] LIF Nanog ES STAT3 STAT3 Nanog ES LIF-STAT3-Oct4 ES Oct4 ES Nanog [38] ES Oct4 ES Oct4 Nanog ES Mitsui [37] SELEX Nanog Gata6 Nanog ES Nanog 2.3 ES Oct4 Nanog FoxD3 FoxD3 (epiblast) Nanog [5] FoxD3 ES Guo [6] FoxD3 Oct4 Nanog FoxD3 [7-11], ES 1-1 ES ES 3 Oct4 Nanog Oct4 Oct4 ICM(ES ) Oct4 Nanog ICM Oct4 ICM Nanog ICM (epiblast) (Endoderm Mesoderm Ectoderm) Nanog ICM (hypoblast) Oct4 Nanog Sox2 FoxD3 (after implantation) ES LIF ES LIF ES STAT3 STAT3 ES ES Oct4 ES ES Oct4 ES ES ES Nanog ES ES LIF ES ( Gata-4 Gata-6) ES (primitive endoderm) 1 ES Oct4 Nanog FoxD3 STAT3
376 1 ES [16] ES ES ES [12-18] ES Oct4 Nanog Sox2 [39-42] [43] [1] Mintz B, Illmensee K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci USA, 1975, 72: 3585-3589 [2] Illmensee K, Mintz B. Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts. Proc Natl Acad Sci USA, 1976, 73: 549-553 [3] Evans M J, Kaufman M H. Establishment in culture of pluripotential cells from mouse embryos. Nature, 1981 292: 154-156 [4] Capecchi M R. Altering the genome by homologous recombination. Science, 1989, 244: 1288-1292 [5] Thomson J A, Itskovitz-Eldor J, Shapiro S S, et al. Embryonic stem cell lines derived from human blastocysts. Science, 1998, 282: 1145-1147 [6] Scholer H R, Octamania. The POU factors in murine development. Trends Genet, 1991, 7: 323-329 [7] Enst M, Oates A, Dann A R. Gp130 mediated signal transduction in embryonic stem cells involves in activation of JAK and Ras/mitogen activated protein kinase pathways. J Biol Chem, 1996, 271: 30136-30143 [8] Dani C, Chambers I, Johnstore S, et al. Paracrine induction of stem cell renewal by LIF-deficient cells: a new ES cell regulatory pathway. Dev Biol, 1998, 203: 149-162 [9] Enst M, Noyak U, Nicholson S E, et al. The carboxyl-terminal domains of gp130 related cytokine receptors are necessary for suppressing embryonic stem cell differentiation. J Biol Chem, 1999, 274: 9729-9737 [10] Niwa H, Burn T, Chambers I, et al. Self renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev, 1998, 12: 2048-2060 [11] Ying Q L, Nichols I, Chambers I, et al. BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renew in collaboration with Stats. Cell, 2003, 115:281-292 [12] Qi X X, Li T G, Hao J, 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
377 [13] Sato N, Meijer L, Skaltsounis L, et al. Maintainance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmmacological GSK-3 inhibitor. Nat Med, 2004, 10: 55-64 [14] Paling WR, Weadon H, Bone H K, et al. Regulation of embryonic stem cell self-renewal by phosphoinositide 3- kinase-dependent signaling. J Biol Chem, 2004, 279(46): 48063-48070 [15] Chambers I. The molecular basis of pluripotency in mouse embryonic stem cells. Cloning Stem Cells, 2004, 6: 386-391 [16] Cavaleri F, Scholer H R. Nanog: a new recruit to the embryonic stem cell orchestra. Cell, 2003, 113(5): 551-552 [17] Schöler H R, Ruppert S, Suzuki N, et al. New type of POU domain in germ line-specific protein Oct-4. Nature, 1990, 344: 435-439 [18] Pesce M, Scholer H. Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells, 2001, 19: 271-278 [19] Scholer H, Dressler G, Balling R, et al. Oct-4: a germlinespecific transcription factor mapping to the mouse t-complex. EMBO J, 1990, 9: 2185-2195 [20] Nichols J, Zevnik B, Anastassiadis K, et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell, 1998, 95: 379-391 [21] Niwa H, Miyazaki J, Smith A. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet, 2000, 24:372-376. [22] Klemm J D, Rould M A, Aurora R, et al. Crystal structure of the Oct-1 POU domain bound to an octamer site: DNA recognition with tethered DNA-binding modules. Cell, 1994, 77: 21-32 [23] Brehm A, Ohbo K, Scholer H. The carboxy-terminal transactivation domain of Oct-4 acquires cell specificity through the POU domain. Mol Cell Biol, 1997, 17: 154-162 [24] Vigano M A, Staudt L M. Transcriptional activation by Oct-3: evidence for a specific role of the POU-specific domain in mediating functional interaction with Oct-1. Nucleic Acids Res, 1996,24:2112-2118 [25] Liu L M, Roberts R. Silencing of the gene for the b subunit of human chorionic gonadotropin by the embryonic transcription factor Oct-3/4. J Biol Chem, 1996, 271: 16683-16689 [26] Liu L M, Leaman D, Villalta M, et al. Silencing of the gene for the α-subunit of human chorionic gonadotropin by the embryonic transcription factor Oct-3/4. Mol Endocrinol, 1997, 11: 1651-1658 [27] Yamamoto H, Flannery M L, Kupriyanov S, et al. Defective trophoblast functions in mice with a targeted mutation of Ets2. Genes Dev, 1998, 12: 1315-1326 [28] Yuan H, Corbi N, Basilico C, et al. Developmental-specific activity of the FGF-4 enhancer requires the synergistic action of Sox2 and Oct-3. Genes Dev, 1995, 9: 2635-2645 [29] Ambrosetti D C, Basilico C, Dailey L. Synergistic activation of the fibroblast growth factor 4 enhancer by Sox2 and Oct-3 depends on protein-protein interactions facilitated by a specific spatial arrangement of factor binding sites. Mol Cell Biol, 1997, 17: 6321-6329 [30] Ambrosetti D C, Scholer H R, Dailey L, et al. 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 [31] Tomioka M, Nishimoto M, Miyagi S, et al. Identification of Sox-2 regulatory region which is under the control of Oct-3/ 4-Sox-2 complex. Nucleic Acids Res, 2002, 30: 3202-3213 [32] Nishimoto M, Fukushima A, Okuda A, et al. 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 [33] Pesce M, Gross M, Scholer H. In line with our ancestors: Oct- 4 and the mammalian germ. Bioessays, 1998, 20: 722-732 [34] Pesce M, Scholer H. Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells, 2001, 19:271-278 [35] Pesce M, Scholer H. Oct-4: control of totipotency and germline determination. Mol Reprod Dev, 2000, 55: 452-457 [36] Pan G, Chang Z Y, Shooler H, et al. Stem cell pluripotency and transcription factor Oct4. Cell Res, 2002, 12(5-6): 321-329 [37] Mitsui K, Tokuzawa Y, Itoh H, et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell, 2003, 113(5): 631-642 [38] Chambers I, Colby D, Robertson M, et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell, 2003, 113(5): 643-655 [39] Boyer L A, Lee T I, Cole M F, et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell, 2005, 122, 947-956 [40] Loh Y H, Wu Q, Chew J L, et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet, 2006, 38: 431-440 [41] Shi W J, Wang H, Pan G J, et al. Regulation of the pluripotency marker Rex-1 by Nanog and Sox2. J Biol Chem, 2006, 281: 23319-23325 [42] Pan G, Li J, Zhou Y, et al. A negative feedback loop of transcription factors that controls stem cell pluripotency and self-renewal. FASEB J, 2006, 20: 1730-1732 [43] Wang J L, Rao S, Chu J L, et al. A protein interaction network for pluripotency of embryonic stem cells. Nature, 2006, 444: 364-368