Committing the primordial germ cell: An updated molecular perspective

Advanced Review

Haihan Tan, Wee‐Wei Tee

Published Online: Sep 17 2018

DOI: 10.1002/wsbm.1436

Full article on Wiley Online Library: HTML PDF

Can't access this content? Tell your librarian.

The germ line is a crucial cell lineage that is distinct from somatic cells, and solely responsible for the trans‐generational transmission of hereditary information in metazoan sexual reproduction. Primordial germ cells (PGCs)—the precursors to functional germ cells—are among the first cell types to be allocated in embryonic development, and this lineage commitment is a critical event in partitioning germ line and somatic tissues. Classically, mammalian PGC development has been largely informed by investigations on mouse embryos and embryonic stem cells. Recent findings from corresponding nonrodent systems, however, have indicated that murine PGC specification may not be fully archetypal. In this review, we outline the current understanding of molecular mechanisms in PGC specification, emphasizing key transcriptional events, and focus on salient differences between early human and mouse PGC commitment. Beyond these latest findings, we also contemplate the future outlook of inquiries in this field, highlighting the importance of comprehensively understanding early fate decisions that underlie the segregation of this unique lineage. This article is categorized under: Developmental Biology > Stem Cell Biology and Regeneration Biological Mechanisms > Cell Fates Physiology > Mammalian Physiology in Health and Disease

Current outlook of human PGC specification. Combined in vitro and in vivo findings have uncovered a hPGC specification mechanism distinct from that of the mouse. This flowchart includes the main, best‐characterized factors in pro‐hPGC pathways; factors in red are the key elements that differ between mPGC and hPGC development. Of note, SOX17 lies upstream of PRDM1 in the PGC specification circuitry, and the roles of PRDM14 and NANOG in specifying hPGCs are unclear. Additionally, EOMES has yet to be characterized as a molecular player in mPGC commitment, while SOX2 is not expressed in committed hPGCs. PGC; primordial germ cell

[ Normal View | Magnified View ]

A molecular paradigm for mouse PGC specification. (a) In the peri‐gastrulation/implantation mouse embryo, BMP and WNT signals emanate from the posterior ExE, visceral endoderm, and the proximal epiblast itself, impinging and acting on the posterior proximal epiblast. These signals represent competence and inductive modalities to drive receptive epiblast cells towards germ lineage fate. (b) a wealth of in vivo and in vitro data has unveiled the molecular pathways and players through which the mPGC lineage is specified. This flowchart demonstrates the major factors involved. ExE; extraembryonic ectoderm. PGC; primordial germ cell

[ Normal View | Magnified View ]

Anatomical observations of embryonic PGCs. (a) Schematic diagram of the peri‐gastrulation mouse embryo, indicating nascent mPGCs observed in the posterior embryo. (b) Schematic diagram of the mouse embryo at about E9.5, showing migratory, committed mPGCs colonizing the genital ridge. (c) Schematic diagram of the week 3 human embryo, with the earliest observed hPGCs in the yolk sac wall. (d) Schematic diagram of the week 5 to 6 human embryo, indicating migratory hPGCs populating the genital ridge. Diagrams are not to scale. ExE; extraembryonic ectoderm. PGC; primordial germ cell

[ Normal View | Magnified View ]

References

Aramaki,, S., Hayashi,, K., Kurimoto,, K., Ohta,, H., Yabuta,, Y., Iwanari,, H., … Saitou,, M. (2013). A mesodermal factor, T, specifies mouse germ cell fate by directly activating germline determinants. Developmental Cell, 27(5), 516–529.
Arnold,, S. J., Stappert,, J., Bauer,, A., Kispert,, A., Herrmann,, B. G., & Kemler,, R. (2000). Brachyury is a target gene of the Wnt/beta‐catenin signaling pathway. Mechanisms of Development, 91(1–2), 249–258.
Avilion,, A. A., Nicolis,, S. K., Pevny,, L. H., Perez,, L., Vivian,, N., & Lovell‐Badge,, R. (2003). Multipotent cell lineages in early mouse development depend on SOX2 function. Genes %26 Development, 17(1), 126–140.
Beddington,, R. S., & Robertson,, E. J. (1999). Axis development and early asymmetry in mammals. Cell, 96(2), 195–209.
Behringer,, R. R., Wakamiya,, M., Tsang,, T. E., & Tam,, P. P. (2000). A flattened mouse embryo: Leveling the playing field. Genesis, 28(1), 23–30.
Bratt‐Leal,, A. M., Carpenedo,, R. L., & McDevitt,, T. C. (2009). Engineering the embryoid body microenvironment to direct embryonic stem cell differentiation. Biotechnology Progress, 25(1), 43–51.
Brons,, I. G., Smithers,, L. E., Trotter,, M. W., Rugg‐Gunn,, P., Sun,, B., Chuva de Sousa Lopes,, S. M., … Vallier,, L. (2007). Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature, 448(7150), 191–195.
Campolo,, F., Gori,, M., Favaro,, R., Nicolis,, S., Pellegrini,, M., Botti,, F., … Dolci,, S. (2013). Essential role of Sox2 for the establishment and maintenance of the germ cell line. Stem Cells, 31(7), 1408–1421.
Canovas,, S., Campos,, R., Aguilar,, E., & Cibelli,, J. B. (2017). Progress towards human primordial germ cell specification in vitro. Molecular Human Reproduction, 23(1), 4–15.
Chambers,, I., Colby,, D., Robertson,, M., Nichols,, J., Lee,, S., Tweedie,, S., & Smith,, A. (2003). Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell, 113(5), 643–655.
Chambers,, I., Silva,, J., Colby,, D., Nichols,, J., Nijmeijer,, B., Robertson,, M., … Smith,, A. (2007). Nanog safeguards pluripotency and mediates germline development. Nature, 450(7173), 1230–1234.
Chang,, H., & Matzuk,, M. M. (2001). Smad5 is required for mouse primordial germ cell development. Mechanisms of Development, 104(1–2), 61–67.
Chen,, D., Liu,, W., Lukianchikov,, A., Hancock,, G., Zimmerman,, J., Lowe,, M., … Clark,, A. T. (2017). Germline competency of human embryonic stem cells depends on EOMESODERMIN. Biology of Reproduction, 97, 850–861.
Chu,, G. C., Dunn,, N. R., Anderson,, D. C., Oxburgh,, L., & Robertson,, E. J. (2004). Differential requirements for Smad4 in TGFbeta‐dependent patterning of the early mouse embryo. Development, 131(15), 3501–3512.
Clark,, A. T., Bodnar,, M. S., Fox,, M., Rodriquez,, R. T., Abeyta,, M. J., Firpo,, M. T., & Pera,, R. A. (2004). Spontaneous differentiation of germ cells from human embryonic stem cells in vitro. Human Molecular Genetics, 13(7), 727–739.
Costello,, I., Nowotschin,, S., Sun,, X., Mould,, A. W., Hadjantonakis,, A. K., Bikoff,, E. K., & Robertson,, E. J. (2015). Lhx1 functions together with Otx2, Foxa2, and Ldb1 to govern anterior mesendoderm, node, and midline development. Genes %26 Development, 29(20), 2108–2122.
Culty,, M. (2009). Gonocytes, the forgotten cells of the germ cell lineage. Birth Defects Research. Part C, Embryo Today, 87(1), 1–26.
D`Amour,, K. A., Agulnick,, A. D., Eliazer,, S., Kelly,, O. G., Kroon,, E., & Baetge,, E. E. (2005). Efficient differentiation of human embryonic stem cells to definitive endoderm. Nature Biotechnology, 23(12), 1534–1541.
De Felici,, M. (2013). Origin, migration, and proliferation of human primordial germ cells. In G. Coticchio, D. Albertini, & L. De Santis (Eds.), Oogenesis (pp. 19–37). London: Springer.
de Jong,, J., Stoop,, H., Gillis,, A. J., van Gurp,, R. J., van de Geijn,, G. J., Boer,, M., … Looijenga,, L. H. (2008). Differential expression of SOX17 and SOX2 in germ cells and stem cells has biological and clinical implications. The Journal of Pathology, 215(1), 21–30.
de Sousa Lopes,, S. M., Roelen,, B. A., Monteiro,, R. M., Emmens,, R., Lin,, H. Y., Li,, E., … Mummery,, C. L. (2004). BMP signaling mediated by ALK2 in the visceral endoderm is necessary for the generation of primordial germ cells in the mouse embryo. Genes %26 Development, 18(15), 1838–1849.
Deglincerti,, A., Croft,, G. F., Pietila,, L. N., Zernicka‐Goetz,, M., Siggia,, E. D., & Brivanlou,, A. H. (2016). Self‐organization of the in vitro attached human embryo. Nature, 533(7602), 251–254.
Extavour,, C. G., & Akam,, M. (2003). Mechanisms of germ cell specification across the metazoans: Epigenesis and preformation. Development, 130(24), 5869–5884.
Fabre,, P. H., Hautier,, L., Dimitrov,, D., & Douzery,, E. J. (2012). A glimpse on the pattern of rodent diversification: A phylogenetic approach. BMC Evolutionary Biology, 12, 88.
Festuccia,, N., Osorno,, R., Halbritter,, F., Karwacki‐Neisius,, V., Navarro,, P., Colby,, D., … Chambers,, I. (2012). Esrrb is a direct Nanog target gene that can substitute for Nanog function in pluripotent cells. Cell Stem Cell, 11(4), 477–490.
Gafni,, O., Weinberger,, L., Mansour,, A. A., Manor,, Y. S., Chomsky,, E., Ben‐Yosef,, D., … Hanna,, J. H. (2013). Derivation of novel human ground state naive pluripotent stem cells. Nature, 504(7479), 282–286.
Geijsen,, N., Horoschak,, M., Kim,, K., Gribnau,, J., Eggan,, K., & Daley,, G. Q. (2004). Derivation of embryonic germ cells and male gametes from embryonic stem cells. Nature, 427(6970), 148–154.
Gillich,, A., Bao,, S., Grabole,, N., Hayashi,, K., Trotter,, M. W., Pasque,, V., … Surani,, M. A. (2012). Epiblast stem cell‐based system reveals reprogramming synergy of germline factors. Cell Stem Cell, 10(4), 425–439.
Ginsburg,, M., Snow,, M. H., & McLaren,, A. (1990). Primordial germ cells in the mouse embryo during gastrulation. Development, 110(2), 521–528.
Gkountela,, S., Li,, Z., Vincent,, J. J., Zhang,, K. X., Chen,, A., Pellegrini,, M., & Clark,, A. T. (2013). The ontogeny of cKIT+ human primordial germ cells proves to be a resource for human germ line reprogramming, imprint erasure and in vitro differentiation. Nature Cell Biology, 15(1), 113–122.
Gkountela,, S., Zhang,, K. X., Shafiq,, T. A., Liao,, W. W., Hargan‐Calvopina,, J., Chen,, P. Y., & Clark,, A. T. (2015). DNA demethylation dynamics in the human prenatal germline. Cell, 161(6), 1425–1436.
Grabole,, N., Tischler,, J., Hackett,, J. A., Kim,, S., Tang,, F., Leitch,, H. G., … Surani,, M. A. (2013). Prdm14 promotes germline fate and naive pluripotency by repressing FGF signalling and DNA methylation. EMBO Reports, 14(7), 629–637.
Guo,, F., Yan,, L., Guo,, H., Li,, L., Hu,, B., Zhao,, Y., … Qiao,, J. (2015). The transcriptome and DNA methylome landscapes of human primordial germ cells. Cell, 161(6), 1437–1452.
Hara,, K., Kanai‐Azuma,, M., Uemura,, M., Shitara,, H., Taya,, C., Yonekawa,, H., … Kanai,, Y. (2009). Evidence for crucial role of hindgut expansion in directing proper migration of primordial germ cells in mouse early embryogenesis. Developmental Biology, 330(2), 427–439.
Hayashi,, K., Ohta,, H., Kurimoto,, K., Aramaki,, S., & Saitou,, M. (2011). Reconstitution of the mouse germ cell specification pathway in culture by pluripotent stem cells. Cell, 146(4), 519–532.
Hayashi,, K., & Surani,, M. A. (2009). Self‐renewing epiblast stem cells exhibit continual delineation of germ cells with epigenetic reprogramming in vitro. Development, 136(21), 3549–3556.
Hubner,, K., Fuhrmann,, G., Christenson,, L. K., Kehler,, J., Reinbold,, R., De La Fuente,, R., … Scholer,, H. R. (2003). Derivation of oocytes from mouse embryonic stem cells. Science, 300(5623), 1251–1256.
Irie,, N., & Surani,, M. A. (2017). Efficient induction and isolation of human primordial germ cell‐like cells from competent human pluripotent stem cells. Methods in Molecular Biology, 1463, 217–226.
Irie,, N., Tang,, W. W., & Azim Surani,, M. (2014). Germ cell specification and pluripotency in mammals: A perspective from early embryogenesis. Reproductive Medicine and Biology, 13(4), 203–215.
Irie,, N., Weinberger,, L., Tang,, W. W., Kobayashi,, T., Viukov,, S., Manor,, Y. S., … Surani,, M. A. (2015). SOX17 is a critical specifier of human primordial germ cell fate. Cell, 160(1–2), 253–268.
Ishii,, T., & Saitou,, M. (2017). Promoting in vitro gametogenesis research with a social understanding. Trends in Molecular Medicine, 23(11), 985–988.
Johnson,, A. D., & Alberio,, R. (2015). Primordial germ cells: The first cell lineage or the last cells standing? Development, 142(16), 2730–2739.
Johnson,, A. D., Drum,, M., Bachvarova,, R. F., Masi,, T., White,, M. E., & Crother,, B. I. (2003). Evolution of predetermined germ cells in vertebrate embryos: Implications for macroevolution. Evolution %26 Development, 5(4), 414–431.
Kanai‐Azuma,, M., Kanai,, Y., Gad,, J. M., Tajima,, Y., Taya,, C., Kurohmaru,, M., … Hayashi,, Y. (2002). Depletion of definitive gut endoderm in Sox17‐ mutant mice. Development, 129(10), 2367–2379.
Kee,, K., Gonsalves,, J. M., Clark,, A. T., & Pera,, R. A. (2006). Bone morphogenetic proteins induce germ cell differentiation from human embryonic stem cells. Stem Cells and Development, 15(6), 831–837.
Kehler,, J., Tolkunova,, E., Koschorz,, B., Pesce,, M., Gentile,, L., Boiani,, M., et al. (2004). Oct4 is required for primordial germ cell survival. EMBO Reports, 5(11), 1078–1083.
Kinder,, S. J., Tsang,, T. E., Quinlan,, G. A., Hadjantonakis,, A. K., Nagy,, A., & Tam,, P. P. (1999). The orderly allocation of mesodermal cells to the extraembryonic structures and the anteroposterior axis during gastrulation of the mouse embryo. Development, 126(21), 4691–4701.
Kobayashi,, T., Zhang,, H., Tang,, W. W. C., Irie,, N., Withey,, S., Klisch,, D., … Surani,, M. A. (2017). Principles of early human development and germ cell program from conserved model systems. Nature, 546(7658), 416–420.
Kojima,, Y., Kaufman‐Francis,, K., Studdert,, J. B., Steiner,, K. A., Power,, M. D., Loebel,, D. A., … Tam,, P. P. (2014). The transcriptional and functional properties of mouse epiblast stem cells resemble the anterior primitive streak. Cell Stem Cell, 14(1), 107–120.
Kubo,, A., Shinozaki,, K., Shannon,, J. M., Kouskoff,, V., Kennedy,, M., Woo,, S., … Keller,, G. (2004). Development of definitive endoderm from embryonic stem cells in culture. Development, 131(7), 1651–1662.
Kurilo,, L. F. (1981). Oogenesis in antenatal development in man. Human Genetics, 57(1), 86–92.
Kurimoto,, K., Yabuta,, Y., Ohinata,, Y., Shigeta,, M., Yamanaka,, K., & Saitou,, M. (2008). Complex genome‐wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice. Genes %26 Development, 22(12), 1617–1635.
Lawson,, K. A., Dunn,, N. R., Roelen,, B. A., Zeinstra,, L. M., Davis,, A. M., Wright,, C. V., … Hogan,, B. L. (1999). Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes %26 Development, 13(4), 424–436.
Lawson,, K. A., & Hage,, W. J. (1994). Clonal analysis of the origin of primordial germ cells in the mouse. Ciba Foundation Symposium, 182, 68–84 discussion 84‐91.
Leopardo,, N. P., & Vitullo,, A. D. (2017). Early embryonic development and spatiotemporal localization of mammalian primordial germ cell‐associated proteins in the basal rodent Lagostomus maximus. Scientific Reports, 7(1), 594.
Liu,, P., Wakamiya,, M., Shea,, M. J., Albrecht,, U., Behringer,, R. R., & Bradley,, A. (1999). Requirement for Wnt3 in vertebrate axis formation. Nature Genetics, 22(4), 361–365.
Magnusdottir,, E., Dietmann,, S., Murakami,, K., Gunesdogan,, U., Tang,, F., Bao,, S., … Azim Surani,, M. (2013). A tripartite transcription factor network regulates primordial germ cell specification in mice. Nature Cell Biology, 15(8), 905–915.
McKay,, D. G., Hertig,, A. T., Adams,, E. C., & Danziger,, S. (1953). Histochemical observations on the germ cells of human embryos. The Anatomical Record, 117(2), 201–219.
Mitsunaga,, S., Odajima,, J., Yawata,, S., Shioda,, K., Owa,, C., Isselbacher,, K. J., … Shioda,, T. (2017). Relevance of iPSC‐derived human PGC‐like cells at the surface of embryoid bodies to prechemotaxis migrating PGCs. Proceedings of the National Academy of Sciences of the United States of America, 114, E9913–E9922.
Molyneaux,, K., & Wylie,, C. (2004). Primordial germ cell migration. The International Journal of Developmental Biology, 48(5–6), 537–544.
Molyneaux,, K. A., Stallock,, J., Schaible,, K., & Wylie,, C. (2001). Time‐lapse analysis of living mouse germ cell migration. Developmental Biology, 240(2), 488–498.
Mummery,, C. L., Zhang,, J., Ng,, E. S., Elliott,, D. A., Elefanty,, A. G., & Kamp,, T. J. (2012). Differentiation of human embryonic stem cells and induced pluripotent stem cells to cardiomyocytes: A methods overview. Circulation Research, 111(3), 344–358.
Murakami,, K., Gunesdogan,, U., Zylicz,, J. J., Tang,, W. W. C., Sengupta,, R., Kobayashi,, T., … Surani,, M. A. (2016). NANOG alone induces germ cells in primed epiblast in vitro by activation of enhancers. Nature, 529(7586), 403–407.
Nakaki,, F., Hayashi,, K., Ohta,, H., Kurimoto,, K., Yabuta,, Y., & Saitou,, M. (2013). Induction of mouse germ‐cell fate by transcription factors in vitro. Nature, 501(7466), 222–226.
Nichols,, J., & Smith,, A. (2009). Naive and primed pluripotent states. Cell Stem Cell, 4(6), 487–492.
Ohinata,, Y., Ohta,, H., Shigeta,, M., Yamanaka,, K., Wakayama,, T., & Saitou,, M. (2009). A signaling principle for the specification of the germ cell lineage in mice. Cell, 137(3), 571–584.
Ohinata,, Y., Payer,, B., O`Carroll,, D., Ancelin,, K., Ono,, Y., Sano,, M., … Surani,, M. A. (2005). Blimp1 is a critical determinant of the germ cell lineage in mice. Nature, 436(7048), 207–213.
Okamura,, D., Tokitake,, Y., Niwa,, H., & Matsui,, Y. (2008). Requirement of Oct3/4 function for germ cell specification. Developmental Biology, 317(2), 576–584.
Pilato,, G., D`Urso,, V., Viglianisi,, F., Sammartano,, F., Sabella,, G., & Lisi,, O. (2013). The problem of the origin of primordial germ cells (PGCs) in vertebrates: Historical review and a possible solution. The International Journal of Developmental Biology, 57(11–12), 809–819.
Rivera‐Perez,, J. A., & Magnuson,, T. (2005). Primitive streak formation in mice is preceded by localized activation of Brachyury and Wnt3. Developmental Biology, 288(2), 363–371.
Rossant,, J. (2015). Mouse and human blastocyst‐derived stem cells: Vive les differences. Development, 142(1), 9–12.
Saitou,, M., & Yamaji,, M. (2012). Primordial germ cells in mice. Cold Spring Harbor Perspectives in Biology, 4(11), pii:a008375.
Sarkar,, A., & Hochedlinger,, K. (2013). The sox family of transcription factors: Versatile regulators of stem and progenitor cell fate. Cell Stem Cell, 12(1), 15–30.
Sasaki,, K., Nakamura,, T., Okamoto,, I., Yabuta,, Y., Iwatani,, C., Tsuchiya,, H., … Saitou,, M. (2016). The germ cell fate of cynomolgus monkeys is specified in the nascent amnion. Developmental Cell, 39(2), 169–185.
Sasaki,, K., Yokobayashi,, S., Nakamura,, T., Okamoto,, I., Yabuta,, Y., Kurimoto,, K., … Saitou,, M. (2015). Robust in vitro induction of human germ cell fate from pluripotent stem cells. Cell Stem Cell, 17(2), 178–194.
Scholer,, H. R., Dressler,, G. R., Balling,, R., Rohdewohld,, H., & Gruss,, P. (1990). Oct‐4: A germline‐specific transcription factor mapping to the mouse t‐complex. The EMBO Journal, 9(7), 2185–2195.
Shahbazi,, M. N., Jedrusik,, A., Vuoristo,, S., Recher,, G., Hupalowska,, A., Bolton,, V., … Zernicka‐Goetz,, M. (2016). Self‐organization of the human embryo in the absence of maternal tissues. Nature Cell Biology, 18(6), 700–708.
Song,, L., Chen,, J., Peng,, G., Tang,, K., & Jing,, N. (2016). Dynamic heterogeneity of Brachyury in mouse epiblast stem cells mediates distinct response to extrinsic bone morphogenetic protein (BMP) signaling. The Journal of Biological Chemistry, 291(29), 15212–15225.
Sugawa,, F., Arauzo‐Bravo,, M. J., Yoon,, J., Kim,, K. P., Aramaki,, S., Wu,, G., … Scholer,, H. R. (2015). Human primordial germ cell commitment in vitro associates with a unique PRDM14 expression profile. The EMBO Journal, 34(8), 1009–1024.
Tada,, S., Era,, T., Furusawa,, C., Sakurai,, H., Nishikawa,, S., Kinoshita,, M., … Chiba,, T. (2005). Characterization of mesendoderm: A diverging point of the definitive endoderm and mesoderm in embryonic stem cell differentiation culture. Development, 132(19), 4363–4374.
Tam,, P. P., & Beddington,, R. S. (1987). The formation of mesodermal tissues in the mouse embryo during gastrulation and early organogenesis. Development, 99(1), 109–126.
Tam,, P. P., & Snow,, M. H. (1981). Proliferation and migration of primordial germ cells during compensatory growth in mouse embryos. Journal of Embryology and Experimental Morphology, 64, 133–147.
Tang,, W. W., Dietmann,, S., Irie,, N., Leitch,, H. G., Floros,, V. I., Bradshaw,, C. R., … Surani,, M. A. (2015). A unique gene regulatory network resets the human germline epigenome for development. Cell, 161(6), 1453–1467.
Toyooka,, Y., Tsunekawa,, N., Akasu,, R., & Noce,, T. (2003). Embryonic stem cells can form germ cells in vitro. Proceedings of the National Academy of Sciences of the United States of America, 100(20), 11457–11462.
Tremblay,, K. D., Dunn,, N. R., & Robertson,, E. J. (2001). Mouse embryos lacking Smad1 signals display defects in extra‐embryonic tissues and germ cell formation. Development, 128(18), 3609–3621.
Tsuneyoshi,, N., Sumi,, T., Onda,, H., Nojima,, H., Nakatsuji,, N., & Suemori,, H. (2008). PRDM14 suppresses expression of differentiation marker genes in human embryonic stem cells. Biochemical and Biophysical Research Communications, 367(4), 899–905.
Turner,, D. A., Rue,, P., Mackenzie,, J. P., Davies,, E., & Martinez Arias,, A. (2014). Brachyury cooperates with Wnt/beta‐catenin signalling to elicit primitive‐streak‐like behaviour in differentiating mouse embryonic stem cells. BMC Biology, 12, 63.
Tzouanacou,, E., Wegener,, A., Wymeersch,, F. J., Wilson,, V., & Nicolas,, J. F. (2009). Redefining the progression of lineage segregations during mammalian embryogenesis by clonal analysis. Developmental Cell, 17(3), 365–376.
Vallier,, L., Reynolds,, D., & Pedersen,, R. A. (2004). Nodal inhibits differentiation of human embryonic stem cells along the neuroectodermal default pathway. Developmental Biology, 275(2), 403–421.
Vincent,, S. D., Dunn,, N. R., Sciammas,, R., Shapiro‐Shalef,, M., Davis,, M. M., Calame,, K., … Robertson,, E. J. (2005). 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(6), 1315–1325.
von Meyenn,, F., Berrens,, R. V., Andrews,, S., Santos,, F., Collier,, A. J., Krueger,, F., … Reik,, W. (2016). Comparative principles of DNA methylation reprogramming during human and mouse in vitro primordial germ cell specification. Developmental Cell, 39(1), 104–115.
Wang,, H., Xiang,, J., Zhang,, W., Li,, J., Wei,, Q., Zhong,, L., … Han,, J. (2016). Induction of germ cell‐like cells from porcine induced pluripotent stem cells. Scientific Reports, 6, 27256.
Wang,, Q., Zou,, Y., Nowotschin,, S., Kim,, S. Y., Li,, Q. V., Soh,, C. L., … Massagué,, J. (2017). The p53 family coordinates Wnt and nodal inputs in Mesendodermal differentiation of embryonic stem cells. Cell Stem Cell, 20(1), 70–86.
Weber,, S., Eckert,, D., Nettersheim,, D., Gillis,, A. J., Schafer,, S., Kuckenberg,, P., … Schorle,, H. (2010). Critical function of AP‐2 gamma/TCFAP2C in mouse embryonic germ cell maintenance. Biology of Reproduction, 82(1), 214–223.
Weismann,, A., Parker,, W. N., & Rōnníeldt,, H. (1893). The germ‐plasm: A theory of heredity. New York, NY: C. Scribner`s.
Whittle,, C. A., & Extavour,, C. G. (2017). Causes and evolutionary consequences of primordial germ‐cell specification mode in metazoans. Proceedings of the National Academy of Sciences of the United States of America, 114(23), 5784–5791.
Yabuta,, Y., Kurimoto,, K., Ohinata,, Y., Seki,, Y., & Saitou,, M. (2006). Gene expression dynamics during germline specification in mice identified by quantitative single‐cell gene expression profiling. Biology of Reproduction, 75(5), 705–716.
Yamaguchi,, S., Kurimoto,, K., Yabuta,, Y., Sasaki,, H., Nakatsuji,, N., Saitou,, M., & Tada,, T. (2009). Conditional knockdown of Nanog induces apoptotic cell death in mouse migrating primordial germ cells. Development, 136(23), 4011–4020.
Yamaji,, M., Seki,, Y., Kurimoto,, K., Yabuta,, Y., Yuasa,, M., Shigeta,, M., … Saitou,, M. (2008). Critical function of Prdm14 for the establishment of the germ cell lineage in mice. Nature Genetics, 40(8), 1016–1022.
Ying,, Y., Liu,, X. M., Marble,, A., Lawson,, K. A., & Zhao,, G. Q. (2000). Requirement of Bmp8b for the generation of primordial germ cells in the mouse. Molecular Endocrinology, 14(7), 1053–1063.
Ying,, Y., & Zhao,, G. Q. (2001). Cooperation of endoderm‐derived BMP2 and extraembryonic ectoderm‐derived BMP4 in primordial germ cell generation in the mouse. Developmental Biology, 232(2), 484–492.
Yokobayashi,, S., Okita,, K., Nakagawa,, M., Nakamura,, T., Yabuta,, Y., Yamamoto,, T., & Saitou,, M. (2017). Clonal variation of human induced pluripotent stem cells for induction into the germ cell fate. Biology of Reproduction, 96(6), 1154–1166.
Zhang,, M., Leitch,, H. G., Tang,, W. W. C., Festuccia,, N., Hall‐Ponsele,, E., Nichols,, J., … Chambers,, I. (2018). Esrrb complementation rescues development of Nanog‐ germ cells. Cell Reports, 22(2), 332–339.

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

Committing the primordial germ cell: An updated molecular perspective

Browse by Topic

Access to this WIREs title is by subscription only.

The latest WIREs articles in your inbox