Ohinata, Y. et al. A signaling principle for the specification of the germ cell lineage in mice. Cell 137, 571–584 (2009).
A comprehensive signalling study that shows that BMP–phosphorylated SMAD (pSMAD) and WNT3 signalling pathways are indispensable for mPGC specification from the post-implantation epiblast during a restricted time window.
Ohinata, Y. et al. Blimp1 is a critical determinant of the germ cell lineage in mice. Nature 436, 207–213 (2005).
Yamaji, M. et al. Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nat. Genet. 40, 1016–1022 (2008).
This paper shows that Prdm14 is crucial for the upregulation of pluripotency genes and the initiation of epigenetic reprogramming during mPGC specification.
Weber, S. et al. Critical function of AP-2γ/TCFAP2C in mouse embryonic germ cell maintenance. Biol. Reprod. 82, 214–223 (2010).
This article shows that Tfap2c, together with Prdm1, represses mesodermal gene expression during mPGC specification.
Magnusdottir, E. et al. A tripartite transcription factor network regulates primordial germ cell specification in mice. Nat. Cell Biol. 15, 905–915 (2013).
Magnusdottir, E. & Surani, M. A. How to make a primordial germ cell. Development 141, 245–252 (2014).
Nakaki, F. et al. Induction of mouse germ-cell fate by transcription factors in vitro. Nature 501, 222–226 (2013).
This study, along with reference 5, shows that overexpression of Prdm1, Tfap2c and/or Prdm14 is sufficient for the induction of mPGC fate.
Lawson, K. A. & Hage, W. J. Clonal analysis of the origin of primordial germ cells in the mouse. Ciba Found. Symp. 182, 68–84; discussion 84–91 (1994).
Seisenberger, S. et al. The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells. Mol. Cell 48, 849–862 (2012).
Hackett, J. A. et al. Germline DNA demethylation dynamics and imprint erasure through 5-hydroxymethylcytosine. Science 339, 448–452 (2013).
Guibert, S., Forne, T. & Weber, M. Global profiling of DNA methylation erasure in mouse primordial germ cells. Genome Res. 22, 633–641 (2012).
References 9–11 describe the detailed genome-wide DNA demethylation dynamics in mPGCs.
Hajkova, P. et al. Epigenetic reprogramming in mouse primordial germ cells. Mech. Dev. 117, 15–23 (2002).
Lee, J. et al. Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells. Development 129, 1807–1817 (2002).
Sugimoto, M. & Abe, K. X chromosome reactivation initiates in nascent primordial germ cells in mice. PLoS Genet. 3, e116 (2007).
Chuva de Sousa Lopes, S. M. et al. X chromosome activity in mouse XX primordial germ cells. PLoS Genet. 4, e30 (2008).
Tam, P. P., Zhou, S. X. & Tan, S. S. X-chromosome activity of the mouse primordial germ cells revealed by the expression of an X-linked lacZ transgene. Development 120, 2925–2932 (1994).
Monk, M. & McLaren, A. X-chromosome activity in foetal germ cells of the mouse. J. Embryol. Exp. Morphol. 63, 75–84 (1981).
Seki, Y. et al. Cellular dynamics associated with the genome-wide epigenetic reprogramming in migrating primordial germ cells in mice. Development 134, 2627–2638 (2007).
Seki, Y. et al. Extensive and orderly reprogramming of genome-wide chromatin modifications associated with specification and early development of germ cells in mice. Dev. Biol. 278, 440–458 (2005).
McLaren, A. Primordial germ cells in the mouse. Dev. Biol. 262, 1–15 (2003).
De Felici, M. in Oogenesis (eds Coticchio, G., Albertini, D. F. & De Santis, L.) 19–37 (Springer, 2012).
Leitch, H. G., Tang, W. W. & Surani, M. A. Primordial germ-cell development and epigenetic reprogramming in mammals. Curr. Top. Dev. Biol. 104, 149–187 (2013).
Fuss, A. Über extraregionare Geschlechtszellen bei einem menschlichen Embryo von 4 Wochen. Anat. Am. 39, 407–409 (in German) (1911).
Witschi, E. Migration of the germ cells of human embryos from the yolk sac to the primitive gonadal folds. Contrib. Embryol. 32, 67–80 (1948).
Extavour, C. G. & Akam, M. Mechanisms of germ cell specification across the metazoans: epigenesis and preformation. Development 130, 5869–5884 (2003).
Weismann, A., Parker, W. N. & Rönnfeldt, H. The Germ-plasm: A Theory of Heredity (Scribner, 1893).
Chatfield, J. et al. Stochastic specification of primordial germ cells from mesoderm precursors in axolotl embryos. Development 141, 2429–2440 (2014).
Ewen-Campen, B., Donoughe, S., Clarke, D. N. & Extavour, C. G. Germ cell specification requires zygotic mechanisms rather than germ plasm in a basally branching insect. Curr. Biol. 23, 835–842 (2013).
Tam, P. P. & Loebel, D. A. Gene function in mouse embryogenesis: get set for gastrulation. Nat. Rev. Genet. 8, 368–381 (2007).
Aramaki, S. et al. A mesodermal factor, T, specifies mouse germ cell fate by directly activating germline determinants. Dev. Cell 27, 516–529 (2013).
Ying, Y. & Zhao, G. Q. Cooperation of endoderm-derived BMP2 and extraembryonic ectoderm-derived BMP4 in primordial germ cell generation in the mouse. Dev. Biol. 232, 484–492 (2001).
Lawson, K. A. et al. Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes Dev. 13, 424–436 (1999).
Ying, Y., Liu, X. M., Marble, A., Lawson, K. A. & Zhao, G. Q. Requirement of Bmp8b for the generation of primordial germ cells in the mouse. Mol. Endocrinol. 14, 1053–1063 (2000).
de Sousa Lopes, S. M. et al. BMP signaling mediated by ALK2 in the visceral endoderm is necessary for the generation of primordial germ cells in the mouse embryo. Genes Dev. 18, 1838–1849 (2004).
Tremblay, K. D., Dunn, N. R. & Robertson, E. J. Mouse embryos lacking Smad1 signals display defects in extra-embryonic tissues and germ cell formation. Development 128, 3609–3621 (2001).
Chu, G. C., Dunn, N. R., Anderson, D. C., Oxburgh, L. & Robertson, E. J. Differential requirements for Smad4 in TGFβ-dependent patterning of the early mouse embryo. Development 131, 3501–3512 (2004).
Chang, H. & Matzuk, M. M. Smad5 is required for mouse primordial germ cell development. Mech. Dev. 104, 61–67 (2001).
Liu, P. et al. Requirement for Wnt3 in vertebrate axis formation. Nat. Genet. 22, 361–365 (1999).
Brennan, J. et al. Nodal signalling in the epiblast patterns the early mouse embryo. Nature 411, 965–969 (2001).
Beddington, R. S. & Robertson, E. J. Axis development and early asymmetry in mammals. Cell 96, 195–209 (1999).
Behringer, R. R., Wakamiya, M., Tsang, T. E. & Tam, P. P. A flattened mouse embryo: leveling the playing field. Genesis 28, 23–30 (2000).
Hopf, C., Viebahn, C. & Puschel, B. BMP signals and the transcriptional repressor BLIMP1 during germline segregation in the mammalian embryo. Dev. Genes Evol. 221, 209–223 (2011).
Idkowiak, J., Weisheit, G., Plitzner, J. & Viebahn, C. Hypoblast controls mesoderm generation and axial patterning in the gastrulating rabbit embryo. Dev. Genes Evol. 214, 591–605 (2004).
Valdez Magana, G., Rodriguez, A., Zhang, H., Webb, R. & Alberio, R. Paracrine effects of embryo-derived FGF4 and BMP4 during pig trophoblast elongation. Dev. Biol. 387, 15–27 (2014).
Irie, N. et al. SOX17 Is a critical specifier of human primordial germ cell fate. Cell 160, 253–268 (2015).
This paper shows robust in vitro induction of hPGCLCs from germline-competent hES cells and illustrates that SOX17 is essential for hPGC specification.
Kee, K., Gonsalves, J. M., Clark, A. T. & Pera, R. A. Bone morphogenetic proteins induce germ cell differentiation from human embryonic stem cells. Stem Cells Dev. 15, 831–837 (2006).
Sasaki, K. et al. Robust in vitro induction of human germ cell fate from pluripotent stem cells. Cell Stem Cell 17, 178–194 (2015).
Tam, P. P. & Zhou, S. X. The allocation of epiblast cells to ectodermal and germ-line lineages is influenced by the position of the cells in the gastrulating mouse embryo. Dev. Biol. 178, 124–132 (1996).
Hayashi, K., Ohta, H., Kurimoto, K., Aramaki, S. & Saitou, M. Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Cell 146, 519–532 (2011).
This paper shows robust in vitro induction of mPGCLCs from ground-state mES cells through a post-implantation epiblast-like state.
Ying, Q. L. et al. The ground state of embryonic stem cell self-renewal. Nature 453, 519–523 (2008).
Boroviak, T., Loos, R., Bertone, P., Smith, A. & Nichols, J. The ability of inner-cell-mass cells to self-renew as embryonic stem cells is acquired following epiblast specification. Nat. Cell Biol. 16, 516–528 (2014).
Hayashi, K. et al. Offspring from oocytes derived from in vitro primordial germ cell-like cells in mice. Science 338, 971–975 (2012).
Kee, K., Angeles, V. T., Flores, M., Nguyen, H. N. & Reijo Pera, R. A. Human DAZL, DAZ and BOULE genes modulate primordial germ-cell and haploid gamete formation. Nature 462, 222–225 (2009).
Wu, J. & Izpisua Belmonte, J. C. Dynamic pluripotent stem cell states and their applications. Cell Stem Cell 17, 509–525 (2015).
Weinberger, L., Ayyash, M., Novershtern, N. & Hanna, J. H. Dynamic stem cell states: naive to primed pluripotency in rodents and humans. Nat. Rev. Mol. Cell Biol. 17, 155–169 (2016).
Gafni, O. et al. Derivation of novel human ground state naive pluripotent stem cells. Nature 504, 282–286 (2013).
Tang, W. W. et al. A unique gene regulatory network resets the human germline epigenome for development. Cell 161, 1453–1467 (2015).
Blakeley, P. et al. Defining the three cell lineages of the human blastocyst by single-cell RNA-seq. Development 142, 3151–3165 (2015).
Pastor, W. A. et al. Naive human pluripotent cells feature a methylation landscape devoid of blastocyst or germline memory. Cell Stem Cell 18, 323–329 (2016).
Takashima, Y. et al. Resetting transcription factor control circuitry toward ground-state pluripotency in human. Cell 158, 1254–1269 (2014).
Sugawa, F. et al. Human primordial germ cell commitment in vitro associates with a unique PRDM14 expression profile. EMBO J. 34, 1009–1024 (2015).
Kojima, Y. et al. The transcriptional and functional properties of mouse epiblast stem cells resemble the anterior primitive streak. Cell Stem Cell 14, 107–120 (2014).
Buecker, C. et al. Reorganization of enhancer patterns in transition from naive to primed pluripotency. Cell Stem Cell 14, 838–853 (2014).
Kurimoto, K. et al. Quantitative dynamics of chromatin remodeling during germ cell specification from mouse embryonic stem cells. Cell Stem Cell 16, 517–532 (2015).
Zylicz, J. J. et al. Chromatin dynamics and the role of G9a in gene regulation and enhancer silencing during early mouse development. eLife 4, e09571 (2015).
Murakami, K. et al. NANOG alone induces germ cells in primed epiblast in vitro by activation of enhancers. Nature 529, 403–407 (2016).
Kurimoto, K. et al. Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice. Genes Dev. 22, 1617–1635 (2008).
Saitou, M., Barton, S. C. & Surani, M. A. A molecular programme for the specification of germ cell fate in mice. Nature 418, 293–300 (2002).
Vincent, S. D. et al. The zinc finger transcriptional repressor Blimp1/Prdm1 is dispensable for early axis formation but is required for specification of primordial germ cells in the mouse. Development 132, 1315–1325 (2005).
This paper and reference 2 show that PRDM1 is the earliest lineage-restricted marker of mPGCs and that it is indispensable for mPGC specification.
Grabole, N. et al. Prdm14 promotes germline fate and naive pluripotency by repressing FGF signalling and DNA methylation. EMBO Rep. 14, 629–637 (2013).
Martins, G. & Calame, K. Regulation and functions of Blimp-1 in T and B lymphocytes. Annu. Rev. Immunol. 26, 133–169 (2008).
Ma, Z., Swigut, T., Valouev, A., Rada-Iglesias, A. & Wysocka, J. Sequence-specific regulator Prdm14 safeguards mouse ESCs from entering extraembryonic endoderm fates. Nat. Struct. Mol. Biol. 18, 120–127 (2011).
Yamaji, M. et al. PRDM14 ensures naive pluripotency through dual regulation of signaling and epigenetic pathways in mouse embryonic stem cells. Cell Stem Cell 12, 368–382 (2013).
Auman, H. J. et al. Transcription factor AP-2γ is essential in the extra-embryonic lineages for early postimplantation development. Development 129, 2733–2747 (2002).
Werling, U. & Schorle, H. Transcription factor gene AP-2γ essential for early murine development. Mol. Cell. Biol. 22, 3149–3156 (2002).
Nady, N. et al. ETO family protein Mtgr1 mediates Prdm14 functions in stem cell maintenance and primordial germ cell formation. eLife 4, e10150 (2015).
Tu, S. et al. Co-repressor CBFA2T2 regulates pluripotency and germline development. Nature 534, 387–390 (2016).
References 76 and 77 show that co-repressor CBFA2T2 interacts with PRDM14 and thus has a role in the regulation of pluripotency and mPGC specification.
Fog, C. K., Galli, G. G. & Lund, A. H. PRDM proteins: important players in differentiation and disease. Bioessays 34, 50–60 (2012).
Scholer, H. R., Dressler, G. R., Balling, R., Rohdewohld, H. & Gruss, P. Oct-4: a germline-specific transcription factor mapping to the mouse t-complex. EMBO J. 9, 2185–2195 (1990).
Yeom, Y. I. et al. Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development 122, 881–894 (1996).
Yabuta, Y., Kurimoto, K., Ohinata, Y., Seki, Y. & Saitou, M. Gene expression dynamics during germline specification in mice identified by quantitative single-cell gene expression profiling. Biol. Reprod. 75, 705–716 (2006).
Sato, M. et al. Identification of PGC7, a new gene expressed specifically in preimplantation embryos and germ cells. Mech. Dev. 113, 91–94 (2002).
Leitch, H. G. et al. Embryonic germ cells from mice and rats exhibit properties consistent with a generic pluripotent ground state. Development 137, 2279–2287 (2010).
Matsui, Y., Zsebo, K. & Hogan, B. L. Derivation of pluripotential embryonic stem cells from murine primordial germ cells in culture. Cell 70, 841–847 (1992).
Durcova-Hills, G., Tang, F., Doody, G., Tooze, R. & Surani, M. A. Reprogramming primordial germ cells into pluripotent stem cells. PLoS ONE 3, e3531 (2008).
Kehler, J. et al. Oct4 is required for primordial germ cell survival. EMBO Rep. 5, 1078–1083 (2004).
Yamaguchi, S. et al. Conditional knockdown of Nanog induces apoptotic cell death in mouse migrating primordial germ cells. Development 136, 4011–4020 (2009).
Chambers, I. et al. Nanog safeguards pluripotency and mediates germline development. Nature 450, 1230–1234 (2007).
Campolo, F. et al. Essential role of Sox2 for the establishment and maintenance of the germ cell line. Stem Cells 31, 1408–1421 (2013).
Yamaguchi, Y. L. et al. Sall4 is essential for mouse primordial germ cell specification by suppressing somatic cell program genes. Stem Cells 33, 289–300 (2015).
Guo, F. et al. The transcriptome and DNA methylome landscapes of human primordial germ cells. Cell 161, 1437–1452 (2015).
This article and reference 57 reveal the transcriptional network and epigenetic reprogramming dynamics in hPGCs isolated from human embryos, using high-quality RNA-seq and bisulfite sequencing (BS-seq) analyses.
Perrett, R. M. et al. The early human germ cell lineage does not express SOX2 during in vivo development or upon in vitro culture. Biol. Reprod. 78, 852–858 (2008).
de Jong, J. et al. Differential expression of SOX17 and SOX2 in germ cells and stem cells has biological and clinical implications. J. Pathol. 215, 21–30 (2008).
Hara, K. et al. Evidence for crucial role of hindgut expansion in directing proper migration of primordial germ cells in mouse early embryogenesis. Dev. Biol. 330, 427–439 (2009).
Sarkar, A. & Hochedlinger, K. The Sox family of transcription factors: versatile regulators of stem and progenitor cell fate. Cell Stem Cell 12, 15–30 (2013).
Kanai-Azuma, M. et al. Depletion of definitive gut endoderm in Sox17-null mutant mice. Development 129, 2367–2379 (2002).
Kim, I., Saunders, T. L. & Morrison, S. J. Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell 130, 470–483 (2007).
Kamachi, Y. & Kondoh, H. Sox proteins: regulators of cell fate specification and differentiation. Development 140, 4129–4144 (2013).
Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat. Biotechnol. 26, 101–106 (2008).
Niakan, K. K. et al. Sox17 promotes differentiation in mouse embryonic stem cells by directly regulating extraembryonic gene expression and indirectly antagonizing self-renewal. Genes Dev. 24, 312–326 (2010).
Seguin, C. A., Draper, J. S., Nagy, A. & Rossant, J. Establishment of endoderm progenitors by SOX transcription factor expression in human embryonic stem cells. Cell Stem Cell 3, 182–195 (2008).
Stefanovic, S. et al. Interplay of Oct4 with Sox2 and Sox17: a molecular switch from stem cell pluripotency to specifying a cardiac fate. J. Cell Biol. 186, 665–673 (2009).
Aksoy, I. et al. Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm. EMBO J. 32, 938–953 (2013).
Niwa, H., Miyazaki, J. & Smith, A. G. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat. Genet. 24, 372–376 (2000).
Maruyama, M., Ichisaka, T., Nakagawa, M. & Yamanaka, S. Differential roles for Sox15 and Sox2 in transcriptional control in mouse embryonic stem cells. J. Biol. Chem. 280, 24371–24379 (2005).
Masui, S. et al. Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells. Nat. Cell Biol. 9, 625–635 (2007).
Chia, N. Y. et al. A genome-wide RNAi screen reveals determinants of human embryonic stem cell identity. Nature 468, 316–320 (2010).
Tsuneyoshi, N. et al. PRDM14 suppresses expression of differentiation marker genes in human embryonic stem cells. Biochem. Biophys. Res. Commun. 367, 899–905 (2008).
Messerschmidt, D. M., Knowles, B. B. & Solter, D. DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos. Genes Dev. 28, 812–828 (2014).
Saitou, M., Kagiwada, S. & Kurimoto, K. Epigenetic reprogramming in mouse pre-implantation development and primordial germ cells. Development 139, 15–31 (2012).
Kobayashi, H. et al. High-resolution DNA methylome analysis of primordial germ cells identifies gender-specific reprogramming in mice. Genome Res. 23, 616–627 (2013).
Sharif, J. et al. The SRA protein Np95 mediates epigenetic inheritance by recruiting Dnmt1 to methylated DNA. Nature 450, 908–912 (2007).
Kagiwada, S., Kurimoto, K., Hirota, T., Yamaji, M. & Saitou, M. Replication-coupled passive DNA demethylation for the erasure of genome imprints in mice. EMBO J. 32, 340–353 (2013).
Ohno, R. et al. A replication-dependent passive mechanism modulates DNA demethylation in mouse primordial germ cells. Development 140, 2892–2903 (2013).
Arand, J. et al. Selective impairment of methylation maintenance is the major cause of DNA methylation reprogramming in the early embryo. Epigenetics Chromatin 8, 1 (2015).
Hackett, J. A., Zylicz, J. J. & Surani, M. A. Parallel mechanisms of epigenetic reprogramming in the germline. Trends Genet. 28, 164–174 (2012).
Yamaguchi, S. et al. Dynamics of 5-methylcytosine and 5-hydroxymethylcytosine during germ cell reprogramming. Cell Res. 23, 329–339 (2013).
Yamaguchi, S., Shen, L., Liu, Y., Sendler, D. & Zhang, Y. Role of Tet1 in erasure of genomic imprinting. Nature 504, 460–464 (2013).
Dawlaty, M. M. et al. Combined deficiency of Tet1 and Tet2 causes epigenetic abnormalities but is compatible with postnatal development. Dev. Cell 24, 310–323 (2013).
Yamaguchi, S. et al. Tet1 controls meiosis by regulating meiotic gene expression. Nature 492, 443–447 (2012).
Gkountela, S. et al. DNA demethylation dynamics in the human prenatal germline. Cell 161, 1425–1436 (2015).
Gaskell, T. L., Esnal, A., Robinson, L. L., Anderson, R. A. & Saunders, P. T. Immunohistochemical profiling of germ cells within the human fetal testis: identification of three subpopulations. Biol. Reprod. 71, 2012–2021 (2004).
Kerr, C. L., Hill, C. M., Blumenthal, P. D. & Gearhart, J. D. Expression of pluripotent stem cell markers in the human fetal ovary. Hum. Reprod. 23, 589–599 (2008).
Kerr, C. L., Hill, C. M., Blumenthal, P. D. & Gearhart, J. D. Expression of pluripotent stem cell markers in the human fetal testis. Stem Cells 26, 412–421 (2008).
Wermann, H. et al. Global DNA methylation in fetal human germ cells and germ cell tumours: association with differentiation and cisplatin resistance. J. Pathol. 221, 433–442 (2010).
Smith, Z. D. & Meissner, A. DNA methylation: roles in mammalian development. Nat. Rev. Genet. 14, 204–220 (2013).
Tsumura, A. et al. Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b. Genes Cells 11, 805–814 (2006).
Brinkman, A. B. et al. Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk. Genome Res. 22, 1128–1138 (2012).
Walter, M., Teissandier, A., Perez-Palacios, R. & Bourc'his, D. An epigenetic switch ensures transposon repression upon dynamic loss of DNA methylation in embryonic stem cells. eLife 5, e11418 (2016).
This paper shows that repressive chromatin modifications repress retrotransposons and safeguard genome stability during chemical-induced global DNA demethylation in mES cells.
Ancelin, K. et al. Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells. Nat. Cell Biol. 8, 623–630 (2006).
Ng, J. H. et al. In vivo epigenomic profiling of germ cells reveals germ cell molecular signatures. Dev. Cell 24, 324–333 (2013).
Liu, S. et al. Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells. Genes Dev. 28, 2041–2055 (2014).
Kim, S. et al. PRMT5 protects genomic integrity during global DNA demethylation in primordial germ cells and preimplantation embryos. Mol. Cell 56, 564–579 (2014).
Guo, H. et al. The DNA methylation landscape of human early embryos. Nature 511, 606–610 (2014).
Smith, Z. D. et al. DNA methylation dynamics of the human preimplantation embryo. Nature 511, 611–615 (2014).
Lane, N. et al. Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 35, 88–93 (2003).
Jeltsch, A. & Jurkowska, R. Z. New concepts in DNA methylation. Trends Biochem. Sci. 39, 310–318 (2014).
Wolf, G., Greenberg, D. & Macfarlan, T. S. Spotting the enemy within: targeted silencing of foreign DNA in mammalian genomes by the Krüppel-associated box zinc finger protein family. Mob. DNA 6, 17 (2015).
Jacobs, F. M. et al. An evolutionary arms race between KRAB zinc-finger genes ZNF91/93 and SVA/L1 retrotransposons. Nature 516, 242–245 (2014).
Li, X. et al. A maternal-zygotic effect gene, Zfp57, maintains both maternal and paternal imprints. Dev. Cell 15, 547–557 (2008).
Mackay, D. J. et al. Hypomethylation of multiple imprinted loci in individuals with transient neonatal diabetes is associated with mutations in ZFP57. Nat. Genet. 40, 949–951 (2008).
Williams, Z. et al. Discovery and characterization of piRNAs in the human fetal ovary. Cell Rep. 13, 854–863 (2015).
Baudat, F. et al. PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice. Science 327, 836–840 (2010).
Daxinger, L. & Whitelaw, E. Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat. Rev. Genet. 13, 153–162 (2012).
Bohacek, J. & Mansuy, I. M. Molecular insights into transgenerational non-genetic inheritance of acquired behaviours. Nat. Rev. Genet. 16, 641–652 (2015).
Heard, E. & Martienssen, R. A. Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157, 95–109 (2014).
Surani, M. A., Barton, S. C. & Norris, M. L. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature 308, 548–550 (1984).
McGrath, J. & Solter, D. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell 37, 179–183 (1984).
Radford, E. J. et al. In utero undernourishment perturbs the adult sperm methylome and intergenerational metabolism. Science 345, 1255903 (2014).
Shea, J. M. et al. Genetic and epigenetic variation, but not diet, shape the sperm methylome. Dev. Cell 35, 750–758 (2015).
Chen, Q. et al. Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351, 397–400 (2016).
Sharma, U. et al. Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351, 391–396 (2016).
Johnson, A. D. & Alberio, R. Primordial germ cells: the first cell lineage or the last cells standing? Development 142, 2730–2739 (2015).
Zhou, Q. et al. Complete meiosis from embryonic stem cell-derived germ cells in vitro. Cell Stem Cell 18, 330–340 (2016).
Zhang, X. et al. Pax6 is a human neuroectoderm cell fate determinant. Cell Stem Cell 7, 90–100 (2010).
Rossant, J. & Tam, P. P. Blastocyst lineage formation, early embryonic asymmetries and axis patterning in the mouse. Development 136, 701–713 (2009).
De Paepe, C., Krivega, M., Cauffman, G., Geens, M. & Van de Velde, H. Totipotency and lineage segregation in the human embryo. Mol. Hum. Reprod. 20, 599–618 (2014).
Niakan, K. K. & Eggan, K. Analysis of human embryos from zygote to blastocyst reveals distinct gene expression patterns relative to the mouse. Dev. Biol. 375, 54–64 (2013).
O'Leary, T. et al. Tracking the progression of the human inner cell mass during embryonic stem cell derivation. Nat. Biotechnol. 30, 278–282 (2012).
Bedzhov, I. & Zernicka-Goetz, M. Self-organizing properties of mouse pluripotent cells initiate morphogenesis upon implantation. Cell 156, 1032–1044 (2014).
Moore, K. L., Persaud, T. V. N. & Torchia, M. G. The Developing Human: Clinically Oriented Embryology (Elsevier/Saunders, 2013).
Hackett, J. A. & Surani, M. A. Regulatory principles of pluripotency: from the ground state up. Cell Stem Cell 15, 416–430 (2014).
Evans, M. J. & Kaufman, M. H. Establishment in culture of pluripotential cells from mouse embryos. Nature 292, 154–156 (1981).
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 78, 7634–7638 (1981).
Brons, I. G. et al. Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 448, 191–195 (2007).
Tesar, P. J. et al. New cell lines from mouse epiblast share defining features with human embryonic stem cells. Nature 448, 196–199 (2007).
Huang, Y., Osorno, R., Tsakiridis, A. & Wilson, V. In vivo differentiation potential of epiblast stem cells revealed by chimeric embryo formation. Cell Rep. 2, 1571–1578 (2012).
Toyooka, Y., Tsunekawa, N., Akasu, R. & Noce, T. Embryonic stem cells can form germ cells in vitro. Proc. Natl Acad. Sci. USA 100, 11457–11462 (2003).
Hubner, K. et al. Derivation of oocytes from mouse embryonic stem cells. Science 300, 1251–1256 (2003).
Hayashi, K. & Surani, M. A. Self-renewing epiblast stem cells exhibit continual delineation of germ cells with epigenetic reprogramming in vitro. Development 136, 3549–3556 (2009).
Thomson, J. A. et al. Embryonic stem cell lines derived from human blastocysts. Science 282, 1145–1147 (1998).
Nichols, J. & Smith, A. Naive and primed pluripotent states. Cell Stem Cell 4, 487–492 (2009).
Vallier, L., Alexander, M. & Pedersen, R. A. Activin/Nodal and FGF pathways cooperate to maintain pluripotency of human embryonic stem cells. J. Cell Sci. 118, 4495–4509 (2005).
Son, M. Y., Choi, H., Han, Y. M. & Cho, Y. S. Unveiling the critical role of REX1 in the regulation of human stem cell pluripotency. Stem Cells 31, 2374–2387 (2013).
Clark, A. T. et al. Spontaneous differentiation of germ cells from human embryonic stem cells in vitro. Hum. Mol. Genet. 13, 727–739 (2004).
Rao, J. et al. Stepwise clearance of repressive roadblocks drives cardiac induction in human ESCs. Cell Stem Cell 18, 341–353 (2016).
Lin, I. Y. et al. Suppression of the SOX2 neural effector gene by PRDM1 promotes human germ cell fate in embryonic stem cells. Stem Cell Rep. 2, 189–204 (2014).
Du, J., Johnson, L. M., Jacobsen, S. E. & Patel, D. J. DNA methylation pathways and their crosstalk with histone methylation. Nat. Rev. Mol. Cell Biol. 16, 519–532 (2015).
Gkountela, S. et al. The ontogeny of cKIT+ human primordial germ cells proves to be a resource for human germ line reprogramming, imprint erasure and in vitro differentiation. Nat. Cell Biol. 15, 113–122 (2013).