Abstract
Through proliferation and differentiation, a single cell, the zygote, can give rise to a complex organism composed of many types of cells. Up to the eight-cell embryo stage, the blastomeres are morphologically identical and distributed symmetrically in the mammalian embryo. Functionally, in some species, they are all totipotent. However, due to the compaction of blastomeres and the asymmetrical cell division at the late phase of the eight-cell embryo, the blastomeres of the morula are no longer identical. During the transition from morula to blastocyst, blastomeres differentiate, resulting in the first cell fate decision in embryogenesis, namely, the segregation of the inner cell mass and the trophectoderm. In this review, we will discuss the regulatory mechanisms essential for the cell fate choice during blastocyst development, including transcriptional regulation, epigenetic regulation, microRNAs, and signal transduction.
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References
Tarkowski AK . Experiments on the development of isolated blastomers of mouse eggs. Nature 1959; 184:1286–1287.
Rossant J . Postimplantation development of blastomeres isolated from 4- and 8-cell mouse eggs. J Embryol Exp Morphol 1976; 36:283–290.
Tarkowski AK, Wroblewska J . Development of blastomeres of mouse eggs isolated at the 4- and 8-cell stage. J Embryol Exp Morphol 1967; 18:155–180.
Kelly SJ . Studies of the developmental potential of 4- and 8-cell stage mouse blastomeres. J Exp Zool 1977; 200:365–376.
Ralston A, Rossant J . Genetic regulation of stem cell origins in the mouse embryo. Clin Genet 2005; 68:106–112.
Rossant J . Lineage development and polar asymmetries in the peri-implantation mouse blastocyst. Semin Cell Dev Biol 2004; 15:573–581.
Piotrowska-Nitsche K, Zernicka-Goetz M . Spatial arrangement of individual 4-cell stage blastomeres and the order in which they are generated correlate with blastocyst pattern in the mouse embryo. Mech Dev 2005; 122:487–500.
Piotrowska-Nitsche K, Perea-Gomez A, Haraguchi S, Zernicka-Goetz M . Four-cell stage mouse blastomeres have different developmental properties. Development 2005; 132:479–490.
Bischoff M, Parfitt DE, Zernicka-Goetz M . Formation of the embryonic-abembryonic axis of the mouse blastocyst: relationships between orientation of early cleavage divisions and pattern of symmetric/asymmetric divisions. Development 2008; 135:953–962.
Jedrusik A, Parfitt DE, Guo G, et al. Role of Cdx2 and cell polarity in cell allocation and specification of trophectoderm and inner cell mass in the mouse embryo. Genes Dev 2008; 22:2692–2706.
Torres-Padilla ME, Parfitt DE, Kouzarides T, Zernicka-Goetz M . Histone arginine methylation regulates pluripotency in the early mouse embryo. Nature 2007; 445:214–218.
Kurotaki Y, Hatta K, Nakao K, Nabeshima Y, Fujimori T . Blastocyst axis is specified independently of early cell lineage but aligns with the ZP shape. Science 2007; 316:719–723.
Plusa B, Frankenberg S, Chalmers A, et al. Downregulation of Par3 and aPKC function directs cells towards the ICM in the preimplantation mouse embryo. J Cell Sci 2005; 118:505–515.
Thomas FC, Sheth B, Eckert JJ, Bazzoni G, Dejana E, Fleming TP . Contribution of JAM-1 to epithelial differentiation and tight-junction biogenesis in the mouse preimplantation embryo. J Cell Sci 2004; 117:5599–5608.
Yamanaka Y, Ralston A, Stephenson RO, Rossant J . Cell and molecular regulation of the mouse blastocyst. Dev Dyn 2006; 235:2301–2314.
Handyside AH . Time of commitment of inside cells isolated from preimplantation mouse embryos. J Embryol Exp Morphol 1978; 45:37–53.
Spindle AI . Trophoblast regeneration by inner cell masses isolated from cultured mouse embryos. J Exp Zool 1978; 203:483–489.
Rossant J, Lis WT . Potential of isolated mouse inner cell masses to form trophectoderm derivatives in vivo. Dev Biol 1979; 70:255–261.
Suwinska A, Czolowska R, Ozdzenski W, Tarkowski AK . Blastomeres of the mouse embryo lose totipotency after the fifth cleavage division: expression of Cdx2 and Oct4 and developmental potential of inner and outer blastomeres of 16- and 32-cell embryos. Dev Biol 2008; 322:133–144.
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.
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; 113:631–642.
Strumpf D, Mao CA, Yamanaka Y, et al. Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst. Development 2005; 132:2093–2102.
Chambers I, Colby D, Robertson M, et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell 2003; 113:643–655.
Palmieri SL, Peter W, Hess H, Scholer HR . 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.
Dietrich JE, Hiiragi T . Stochastic patterning in the mouse pre-implantation embryo. Development 2007; 134:4219–4231.
Hatano SY, Tada M, Kimura H, et al. Pluripotential competence of cells associated with Nanog activity. Mech Dev 2005; 122:67–79.
Silva J, Nichols J, Theunissen TW, et al. Nanog is the gateway to the pluripotent ground state. Cell 2009; 138:722–737.
Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N, Lovell-Badge R . Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev 2003; 17:126–140.
Boyer LA, Lee TI, Cole MF, et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 2005; 122:947–956.
Yagi R, Kohn MJ, Karavanova I, et al. Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development. Development 2007; 134:3827–3836.
Nishioka N, Yamamoto S, Kiyonari H, et al. Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos. Mech Dev 2008; 125:270–283.
Russ AP, Wattler S, Colledge WH, et al. Eomesodermin is required for mouse trophoblast development and mesoderm formation. Nature 2000; 404:95–99.
Donnison M, Beaton A, Davey HW, Broadhurst R, L'Huillier P, Pfeffer PL . Loss of the extraembryonic ectoderm in Elf5 mutants leads to defects in embryonic patterning. Development 2005; 132:2299–2308.
Niwa H, Toyooka Y, Shimosato D, et al. Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 2005; 123:917–929.
Nishioka N, Inoue K, Adachi K, et al. The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell 2009; 16:398–410.
Loh YH, Wu Q, Chew JL, et al. The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells. Nat Genet 2006; 38:431–440.
Kim J, Chu J, Shen X, Wang J, Orkin SH . An extended transcriptional network for pluripotency of embryonic stem cells. Cell 2008; 132:1049–1061.
Chen X, Xu H, Yuan P, et al. Integration of external signaling pathways with the core transcriptional network in embryonic stem cells. Cell 2008; 133:1106–1117.
Wu Q, Chen X, Zhang J, et al. Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells. J Biol Chem 2006; 281:24090–24094.
Zhang J, Tam WL, Tong GQ, et al. Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nat Cell Biol 2006; 8:1114–1123.
Chen L, Yabuuchi A, Eminli S, et al. Cross-regulation of the Nanog and Cdx2 promoters. Cell Res 2009; 19:1052–1061.
Sakaki-Yumoto M, Kobayashi C, Sato A, et al. The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in anorectal, heart, brain and kidney development. Development 2006; 133:3005–3013.
Yuri S, Fujimura S, Nimura K, et al. Sall4 is essential for stabilization, but not for pluripotency, of embryonic stem cells by repressing aberrant trophectoderm gene expression. Stem Cells 2009; 27:796–805.
Ralston A, Cox BJ, Nishioka N, et al. Gata3 regulates trophoblast development downstream of Tead4 and in parallel to Cdx2. Development 2010; 137:395–403.
Ng RK, Dean W, Dawson C, et al. Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5. Nat Cell Biol 2008; 10:1280–1290.
Home P, Ray S, Dutta D, Bronshteyn I, Larson M, Paul S . GATA3 is selectively expressed in the trophectoderm of peri-implantation embryo and directly regulates Cdx2 gene expression. J Biol Chem 2009; 284:28729–28737.
Morgan HD, Santos F, Green K, Dean W, Reik W . Epigenetic reprogramming in mammals. Hum Mol Genet 2005; 14 Spec No 1:R47–58.
Li E . Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genet 2002; 3:662–673.
Reik W, Santos F, Mitsuya K, Morgan H, Dean W . Epigenetic asymmetry in the mammalian zygote and early embryo: relationship to lineage commitment? Philos Trans R Soc Lond B Biol Sci 2003; 358:1403–1409.
Jenuwein T, Allis CD . Translating the histone code. Science 2001; 293:1074–1080.
Adenot PG, Mercier Y, Renard JP, Thompson EM . Differential H4 acetylation of paternal and maternal chromatin precedes DNA replication and differential transcriptional activity in pronuclei of 1-cell mouse embryos. Development 1997; 124:4615–4625.
Lepikhov K, Walter J . Differential dynamics of histone H3 methylation at positions K4 and K9 in the mouse zygote. BMC Dev Biol 2004; 4:12.
Santos F, Peters AH, Otte AP, Reik W, Dean W . Dynamic chromatin modifications characterise the first cell cycle in mouse embryos. Dev Biol 2005; 280:225–236.
Kourmouli N, Jeppesen P, Mahadevhaiah S, et al. Heterochromatin and tri-methylated lysine 20 of histone H4 in animals. J Cell Sci 2004; 117:2491–2501.
Erhardt S, Su IH, Schneider R, et al. Consequences of the depletion of zygotic and embryonic enhancer of zeste 2 during preimplantation mouse development. Development 2003; 130:4235–4248.
VerMilyea MD, O'Neill LP, Turner BM . Transcription-independent heritability of induced histone modifications in the mouse preimplantation embryo. PLoS One 2009; 4:e6086.
O'Neill LP, VerMilyea MD, Turner BM . Epigenetic characterization of the early embryo with a chromatin immunoprecipitation protocol applicable to small cell populations. Nat Genet 2006; 38:835–841.
Mayer W, Niveleau A, Walter J, Fundele R, Haaf T . Demethylation of the zygotic paternal genome. Nature 2000; 403:501–502.
Santos F, Hendrich B, Reik W, Dean W . Dynamic reprogramming of DNA methylation in the early mouse embryo. Dev Biol 2002; 241:172–182.
Morgan HD, Dean W, Coker HA, Reik W, Petersen-Mahrt SK . Activation-induced cytidine deaminase deaminates 5-methylcytosine in DNA and is expressed in pluripotent tissues: implications for epigenetic reprogramming. J Biol Chem 2004; 279:52353–52360.
Popp C, Dean W, Feng S, et al. Genome-wide erasure of DNA methylation in mouse primordial germ cells is affected by AID deficiency. Nature 2010; 463:1101–1105.
Bhutani N, Brady JJ, Damian M, Sacco A, Corbel SY, Blau HM . Reprogramming towards pluripotency requires AID-dependent DNA demethylation. Nature 2010; 463:1042–1047.
Barreto G, Schafer A, Marhold J, et al. Gadd45a promotes epigenetic gene activation by repair-mediated DNA demethylation. Nature 2007; 445:671–675.
Okada Y, Yamagata K, Hong K, Wakayama T, Zhang Y . A role for the elongator complex in zygotic paternal genome demethylation. Nature 2010; 463:554–558.
Nakamura T, Arai Y, Umehara H, et al. PGC7/Stella protects against DNA demethylation in early embryogenesis. Nat Cell Biol 2007; 9:64–71.
Rougier N, Bourc'his D, Gomes DM, et al. Chromosome methylation patterns during mammalian preimplantation development. Genes Dev 1998; 12:2108–2113.
Carlson LL, Page AW, Bestor TH . Properties and localization of DNA methyltransferase in preimplantation mouse embryos: implications for genomic imprinting. Genes Dev 1992; 6:2536–2541.
Howlett SK, Reik W . Methylation levels of maternal and paternal genomes during preimplantation development. Development 1991; 113:119–127.
Dean W, Santos F, Stojkovic M, et al. Conservation of methylation reprogramming in mammalian development: aberrant reprogramming in cloned embryos. Proc Natl Acad Sci USA 2001; 98:13734–13738.
Santos F, Zakhartchenko V, Stojkovic M, et al. Epigenetic marking correlates with developmental potential in cloned bovine preimplantation embryos. Curr Biol 2003; 13:1116–1121.
Huynh KD, Lee JT . Inheritance of a pre-inactivated paternal X chromosome in early mouse embryos. Nature 2003; 426:857–862.
Okamoto I, Otte AP, Allis CD, Reinberg D, Heard E . Epigenetic dynamics of imprinted X inactivation during early mouse development. Science 2004; 303:644–649.
Mak W, Nesterova TB, de Napoles M, et al. Reactivation of the paternal X chromosome in early mouse embryos. Science 2004; 303:666–669.
Monk M, Harper MI . Sequential X chromosome inactivation coupled with cellular differentiation in early mouse embryos. Nature 1979; 281:311–313.
Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N . Requirement for Xist in X chromosome inactivation. Nature 1996; 379:131–137.
Payer B, Lee JT . X chromosome dosage compensation: how mammals keep the balance. Annu Rev Genet 2008; 42:733–772.
Lee JT, Davidow LS, Warshawsky D . Tsix, a gene antisense to Xist at the X-inactivation centre. Nat Genet 1999; 21:400–404.
Lee JT, Lu N . Targeted mutagenesis of Tsix leads to nonrandom X inactivation. Cell 1999; 99:47–57.
Ogawa Y, Lee JT . Xite, X-inactivation intergenic transcription elements that regulate the probability of choice. Mol Cell 2003; 11:731–743.
Chao W, Huynh KD, Spencer RJ, Davidow LS, Lee JT . CTCF, a candidate trans-acting factor for X-inactivation choice. Science 2002; 295:345–347.
Donohoe ME, Zhang LF, Xu N, Shi Y, Lee JT . Identification of a Ctcf cofactor, Yy1, for the X chromosome binary switch. Mol Cell 2007; 25:43–56.
Heard E, Disteche CM . Dosage compensation in mammals: fine-tuning the expression of the X chromosome. Genes Dev 2006; 20:1848–1867.
Navarro P, Chambers I, Karwacki-Neisius V, et al. Molecular coupling of Xist regulation and pluripotency. Science 2008; 321:1693–1695.
Donohoe ME, Silva SS, Pinter SF, Xu N, Lee JT . The pluripotency factor Oct4 interacts with Ctcf and also controls X-chromosome pairing and counting. Nature 2009; 460:128–132.
Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126:663–676.
Stadtfeld M, Maherali N, Breault DT, Hochedlinger K . Defining molecular cornerstones during fibroblast to iPS cell reprogramming in mouse. Cell Stem Cell 2008; 2:230–240.
Yeap LS, Hayashi K, Surani MA . ERG-associated protein with SET domain (ESET)-Oct4 interaction regulates pluripotency and represses the trophectoderm lineage. Epigenetics Chromatin 2009; 2:12.
Yuan P, Han J, Guo G, et al. Eset partners with Oct4 to restrict extraembryonic trophoblast lineage potential in embryonic stem cells. Genes Dev 2009; 23:2507–2520.
Kloosterman WP, Plasterk RH . The diverse functions of microRNAs in animal development and disease. Dev Cell 2006; 11:441–450.
Tang F, Kaneda M, O'Carroll D, et al. Maternal microRNAs are essential for mouse zygotic development. Genes Dev 2007; 21:644–648.
Yang Y, Bai W, Zhang L, et al. Determination of microRNAs in mouse preimplantation embryos by microarray. Dev Dyn 2008; 237:2315–2327.
Viswanathan SR, Mermel CH, Lu J, Lu CW, Golub TR, Daley GQ . MicroRNA expression during trophectoderm specification. PLoS One 2009; 4:e6143.
Bernstein E, Kim SY, Carmell MA, et al. Dicer is essential for mouse development. Nat Genet 2003; 35:215–217.
Kanellopoulou C, Muljo SA, Kung AL, et al. Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev 2005; 19:489–501.
Murchison EP, Partridge JF, Tam OH, Cheloufi S, Hannon GJ . Characterization of Dicer-deficient murine embryonic stem cells. Proc Natl Acad Sci USA 2005; 102:12135–12140.
Wang Y, Medvid R, Melton C, Jaenisch R, Blelloch R . DGCR8 is essential for microRNA biogenesis and silencing of embryonic stem cell self-renewal. Nat Genet 2007; 39:380–385.
Murchison EP, Stein P, Xuan Z, et al. Critical roles for Dicer in the female germline. Genes Dev 2007; 21:682–693.
Lykke-Andersen K, Gilchrist MJ, Grabarek JB, Das P, Miska E, Zernicka-Goetz M . Maternal Argonaute 2 is essential for early mouse development at the maternal-zygotic transition. Mol Biol Cell 2008; 19:4383–4392.
Houbaviy HB, Murray MF, Sharp PA . Embryonic stem cell-specific MicroRNAs. Dev Cell 2003; 5:351–358.
Blakaj A, Lin H . Piecing together the mosaic of early mammalian development through microRNAs. J Biol Chem 2008; 283:9505–9508.
Judson RL, Babiarz JE, Venere M, Blelloch R . Embryonic stem cell-specific microRNAs promote induced pluripotency. Nat Biotechnol 2009; 27:459–461.
Lin SL, Chang DC, Chang-Lin S, et al. Mir-302 reprograms human skin cancer cells into a pluripotent ES-cell-like state. RNA 2008; 14:2115–2124.
Tay Y, Zhang J, Thomson AM, Lim B, Rigoutsos I . MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 2008; 455:1124–1128.
Xu N, Papagiannakopoulos T, Pan G, Thomson JA, Kosik KS . MicroRNA-145 regulates OCT4, SOX2, and KLF4 and represses pluripotency in human embryonic stem cells. Cell 2009; 137:647–658.
Benetti R, Gonzalo S, Jaco I, et al. A mammalian microRNA cluster controls DNA methylation and telomere recombination via Rbl2-dependent regulation of DNA methyltransferases. Nat Struct Mol Biol 2008; 15:268–279.
Sinkkonen L, Hugenschmidt T, Berninger P, et al. MicroRNAs control de novo DNA methylation through regulation of transcriptional repressors in mouse embryonic stem cells. Nat Struct Mol Biol 2008; 15:259–267.
Yamauchi N, Kiessling AA, Cooper GM . The Ras/Raf signaling pathway is required for progression of mouse embryos through the two-cell stage. Mol Cell Biol 1994; 14:6655–6662.
Natale DR, Paliga AJ, Beier F, D'Souza SJ, Watson AJ . p38 MAPK signaling during murine preimplantation development. Dev Biol 2004; 268:76–88.
Maekawa M, Yamamoto T, Tanoue T, Yuasa Y, Chisaka O, Nishida E . Requirement of the MAP kinase signaling pathways for mouse preimplantation development. Development 2005; 132:1773–1783.
Lu CW, Yabuuchi A, Chen L, Viswanathan S, Kim K, Daley GQ . Ras-MAPK signaling promotes trophectoderm formation from embryonic stem cells and mouse embryos. Nat Genet 2008; 40:921–926.
Nichols J, Silva J, Roode M, Smith A . Suppression of Erk signalling promotes ground state pluripotency in the mouse embryo. Development 2009; 136:3215–3222.
Saba-El-Leil MK, Vella FD, Vernay B, et al. An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development. EMBO Rep 2003; 4:964–968.
Pan D . Hippo signaling in organ size control. Genes Dev 2007; 21:886–897.
Pauken CM, Capco DG . Regulation of cell adhesion during embryonic compaction of mammalian embryos: roles for PKC and beta-catenin. Mol Reprod Dev 1999; 54:135–144.
Pauken CM, Capco DG . The expression and stage-specific localization of protein kinase C isotypes during mouse preimplantation development. Dev Biol 2000; 223:411–421.
Guo X, Wang XF . Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res 2009; 19:71–88.
Acknowledgements
GQD was supported by grants from the National Institutes of Health, the NIH Director's Pioneer Award of the NIH Roadmap for Medical Research, and private funds contributed to the Harvard Stem Cell Institute and the Children's Hospital Stem Cell Program, USA. GQD is a recipient of Clinical Scientist Awards in Translational Research from the Burroughs Wellcome Fund and the Leukemia and Lymphoma Society, and is an Investigator at the Howard Hughes Medical Institute. LC was supported by the National Natural Science Foundation of China (Grant no. 90919009), the National Key Basic Research and Development Program of China (Grant no. 2009CB941000 and 2010CB833603), and the Ministry of Agriculture of China (Grant no. 2009ZX08006-010B and 2009ZX08006-011B).
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Chen, L., Wang, D., Wu, Z. et al. Molecular basis of the first cell fate determination in mouse embryogenesis. Cell Res 20, 982–993 (2010). https://doi.org/10.1038/cr.2010.106
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DOI: https://doi.org/10.1038/cr.2010.106
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