Specification of primordial germ cells

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Primordial germ cells (PGCs), the progenitors of female gametes (oocytes) and male gametes (sperm), are specified and segregated from somatic cells early during mammalian development. In the mouse embryo, precursors of PGCs are present in the proximal epiblast adjacent to the extraembryonic ectoderm before gastrulation (E6.0, pre-streak stage) and PGCs, marked by high alkaline phosphatase activity (Ginsburg et al. 1990), are translocated to the extraembryonic mesoderm at the base of the developing allantois during gastrulation (Lawson and Hage 1994). Subsequently, PGCs are regionalised in the epithelium of the embryonic gut and migrate via the dorsal mesentery of the embryonic gut to the genital ridge. The post-migratory PGCs differentiate into oogonia and spermatogonia in the fetal gonad. In mouse embryos, PGCs are induced by Bmp4 emanating from extraembryonic ectoderm and Wnt3 from the visceral endoderm (reviewed in Bleckwehl and Rada Iglesias 2019). Less is known about the developmental origin of human PGCs and the sources of inducing signaling factors. In the non human primate (Cynomolgus monkey), PGCs are first observed in the amniotic epithelium of the amniotic sac of the pre-gastrulation embryo and remain in the early amnion for an extended period (6 days) (Sasaki et al. 2016). BMP4 is expressed in the amnion and WNT3A is expressed in the cytotrophoblast (Sasaki et al. 2016).
Ex vivo and in vitro studies have been performed to elucidate the specification of human PGCs (reviewed in Hancock et al. 2021). Putative PGCs, identified by immunofluorescence of PGC markers, are induced in ex vivo culture of early blastocysts (E6 days post fertilization, dpf) (Chen et al. 2019, Popovic et al. 2019) and in vitro differentiation of embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) in the presence of BMP4 (Irie et al. 2015, Sasaki et al. 2015, Tang et al. 2015, Chen et al. 2017, Kojima et al. 2017). In both mouse embryos and cultured human cells, competence of the epiblast-like cells to form PGCs in response to BMP4 signals is transient during development, where, in the absence of BMP4, the epiblast-like cells acquire the mesendoderm cell fate (Tang et al. 2015).
For the induction of PGC-like cells from human pluripotent stem cells, the gene network activity that specifies human PGCs is different from that of mouse PGCs. Notably, SOX17, but not Prdm14, is a key factor for the specification of human PGCs. In human PGC precursors, Eomesodermin (EOMES) activates expression of SOX17, the most upstream factor in PGC specification. Similar molecular events are observed in the early PGCs isolated from human embryos and cynomolgus monkeys (Tyser et al. 2021). BMP4 signaling initiates the expression of TFAP2C and SOX17, that in turns initiates expression of PRDM1 (Tang et al. 2015, Kojima et al. 2017, Tang et al. 2022). Together these three key factors, SOX17, TFAP2C, and PRDM1, specify PGCs, activate the PGC program, and repress somatic cell programs, with SOX17 acting as an activator and PRDM1 as a repressor (Tang et al. 2015, Sasaki et al. 2015). Genes activated in PGCs include the pluripotency-related factors POU5F1 (OCT4) and NANOG (but not SOX2), the DNA demethylation factor TET2, and the regulators of cell migration PDPN and CXCR4 (Irie et al. 2015, Sasaki et al. 2015, Chen et al. 2018, Mishra et al. 2021, Tang et al. 2022). PRDM1 represses genes involved in DNA methylation leading to a genome wide DNA demethylation in human PGCs around week 10-11 of development (Guo et al. 2015). In mouse embryonal carcinoma cells, Prdm1 (Blimp1) binds and represses expression of the de novo DNA methylase Dnmt3b and Uhrf1, which interacts with the DNA methylase Dnmt1 (Magnusdottir et al. 2013). PRDM1 in human PGCs similarly represses expression of DNMT3B, DNMT1, and UHRF1 through yet uncharacterized mechanisms (Tang et al. 2015).
Literature References
PubMed ID Title Journal Year
34789876 Single-cell transcriptomic characterization of a gastrulating human embryo

Vallier, L, Nakanoh, S, Mahammadov, E, Tyser, RCV, Srinivas, S, Scialdone, A

Nature 2021
26046444 A Unique Gene Regulatory Network Resets the Human Germline Epigenome for Development

Dietmann, S, Surani, MA, Leitch, HG, Tang, WW, Bradshaw, CR, Chinnery, PF, Hackett, JA, Irie, N, Floros, VI

Cell 2015
28278531 Of Mice and Men: In Vivo and In Vitro Studies of Primordial Germ Cell Specification

DeFalco, T, Kumar, DL

Semin Reprod Med 2017
33470497 Activin A-derived human embryonic stem cells show increased competence to differentiate into primordial germ cell-like cells

Tilleman, L, Menten, B, van Nieuwerburgh, F, Popovic, M, Chuva De Sousa Lopes, SM, Taelman, J, Mishra, S, Van Der Jeught, M, Boel, A, De Sutter, P, Deforce, D, Duthoo, E, Heindryckx, B

Stem Cells 2021
29091993 Germline competency of human embryonic stem cells depends on eomesodermin

Clark, AT, Lowe, MG, Galic, Z, Surani, MA, Kim, R, Hancock, GV, Zimmerman, J, Lukianchikov, A, Irie, N, Liu, W, Jacobsen, SE, Chen, D

Biol Reprod 2017
33722957 Mammalian primordial germ cell specification

Clark, AT, Hancock, GV, Wamaitha, SE, Peretz, L

Development 2021
28985527 Evolutionarily Distinctive Transcriptional and Signaling Programs Drive Human Germ Cell Lineage Specification from Pluripotent Stem Cells

Saitou, M, Nakaki, F, Yamamoto, T, Woltjen, K, Yokobayashi, S, Hotta, A, Sasaki, K, Kojima, Y, Sakai, Y, Nagaoka, S, Yabuta, Y, Nakamura, T

Cell Stem Cell 2017
27573372 Specification and epigenetic programming of the human germ line

Dietmann, S, Surani, MA, Tang, WW, Kobayashi, T, Irie, N

Nat Rev Genet 2016
30590035 The TFAP2C-Regulated OCT4 Naive Enhancer Is Involved in Human Germline Formation

Clark, AT, Ho, J, Kim, R, Pastor, WA, Zimmerman, J, Gell, JJ, Hosohama, L, Liu, W, Jacobsen, SE, Chen, D, Aslanyan, M

Cell Rep 2018
25543152 SOX17 is a critical specifier of human primordial germ cell fate

Dietmann, S, Surani, MA, Viukov, S, Tang, WW, Hanna, JH, Weinberger, L, Manor, YS, Kobayashi, T, Irie, N

Cell 2015
31211841 Human blastocyst outgrowths recapitulate primordial germ cell specification events

De Sutter, P, Popovic, M, Chuva De Sousa Lopes, SM, Taelman, J, Bialecka, M, Van Der Jeught, M, Heindryckx, B, Gomes Fernandes, M

Mol Hum Reprod 2019
31155364 Germ cell reprogramming

Saitou, M, Kurimoto, K

Curr Top Dev Biol 2019
26189426 Robust In Vitro Induction of Human Germ Cell Fate from Pluripotent Stem Cells

Sekiguchi, K, Moritoki, Y, Ohta, H, Kurimoto, K, Yamamoto, T, Nakagawa, M, Yamanaka, S, Mori, T, Saitou, M, Tsuchiya, H, Takahashi, K, Okamoto, I, Yamamoto, T, Woltjen, K, Sakuma, T, Yokobayashi, S, Sasaki, K, Iwatani, C, Nakamura, S, Yabuta, Y, Nakamura, T

Cell Stem Cell 2015
26046443 The Transcriptome and DNA Methylome Landscapes of Human Primordial Germ Cells

Yong, J, Yan, J, Guo, H, Zhang, L, Li, R, Liu, S, Zhao, Y, Hou, Y, Tang, F, Hu, B, Yan, L, Qiao, J, Gao, YQ, Wang, X, Wen, L, Zhang, W, Wei, Y, Hu, Y, Wang, W, Zhu, P, Jin, H, Zhu, X, Ren, Y, Li, L, Guo, F, Li, J, Zhi, X, Zhang, Y

Cell 2015
31875561 Human Primordial Germ Cells Are Specified from Lineage-Primed Progenitors

Kellis, M, Fu, J, Kim, R, Faith, J, Sun, N, Hou, L, Clark, A, Liu, W, Zheng, Y, Tao, Y, Chen, D, Aslanyan, M

Cell Rep 2019
34847550 Epigenetic Regulation during Primordial Germ Cell Development and Differentiation

Ramakrishna, NB, Leitch, HG, Murison, K, Miska, EA

Sex Dev 2021
35411086 Sequential enhancer state remodelling defines human germline competence and specification

Castillo-Venzor, A, Tang, WWC, Surani, MA, Sun, D, Gruhn, WH, Penfold, CA, Kobayashi, T, Irie, N, Morgan, MD

Nat Cell Biol 2022
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