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Primordial germ cell specification: a context-dependent cellular differentiation event [corrected].

Günesdogan U, Magnúsdóttir E, Surani MA - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2014)

Bottom Line: During embryonic development, the foundation of the germline is laid by the specification of primordial germ cells (PGCs) from the postimplantation epiblast via bone morphogenetic protein (BMP) and WNT signalling.However, an unresolved question is how postimplantation epiblast cells acquire the developmental competence for the PGC fate downstream of BMP/WNT signalling.Here, we discuss recent advances on the specification and reprogramming of PGCs thereby highlighting the concept of enhancer function.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK Department of Physiology, Development and Neuroscience, University of Cambridge, Downing St., Cambridge CB2 3DY, UK Wellcome Trust Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.

ABSTRACT
During embryonic development, the foundation of the germline is laid by the specification of primordial germ cells (PGCs) from the postimplantation epiblast via bone morphogenetic protein (BMP) and WNT signalling. While the majority of epiblast cells undergo differentiation towards somatic cell lineages, PGCs initiate a unique cellular programme driven by the cooperation of the transcription factors BLIMP1, PRDM14 and AP2γ. These factors synergistically suppress the ongoing somatic differentiation and drive the re-expression of pluripotency and germ cell-specific genes accompanied by global epigenetic changes. However, an unresolved question is how postimplantation epiblast cells acquire the developmental competence for the PGC fate downstream of BMP/WNT signalling. One emerging concept is that transcriptional enhancers might play a central role in the establishment of developmental competence and the execution of cell fate determination. Here, we discuss recent advances on the specification and reprogramming of PGCs thereby highlighting the concept of enhancer function.

Show MeSH
Embryonic origin of PGCs in vivo and PGC derivation in vitro. The preimplantation blastocyst at E4.5 consists of the embryonic lineage, the epiblast, and two extraembryonic lineages, primitive endoderm and trophectoderm. After implantation at E6.5, signalling from the extraembryonic ectoderm as well as from the visceral endoderm induces a few cells of the proximal epiblast to become PGCs. In vitro, ES cells, which are derived from the preimplantation epiblast, can be differentiated into epiblast-like cells (EpiLCs) with Activin A and basic fibroblast growth factor. EpiLCs, in turn, respond to BMP4 to give rise to functional PGC-like cells. Epiblast stem cells (EpiSCs), which are traditionally derived from the postimplantation epiblast, also give rise to PGC-like cells, but at a low frequency. (Online version in colour.)
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RSTB20130543F1: Embryonic origin of PGCs in vivo and PGC derivation in vitro. The preimplantation blastocyst at E4.5 consists of the embryonic lineage, the epiblast, and two extraembryonic lineages, primitive endoderm and trophectoderm. After implantation at E6.5, signalling from the extraembryonic ectoderm as well as from the visceral endoderm induces a few cells of the proximal epiblast to become PGCs. In vitro, ES cells, which are derived from the preimplantation epiblast, can be differentiated into epiblast-like cells (EpiLCs) with Activin A and basic fibroblast growth factor. EpiLCs, in turn, respond to BMP4 to give rise to functional PGC-like cells. Epiblast stem cells (EpiSCs), which are traditionally derived from the postimplantation epiblast, also give rise to PGC-like cells, but at a low frequency. (Online version in colour.)

Mentions: Mammals specify their PGCs in response to instructive signalling during embryonic development. In mice, the blastocyst differentiates into epiblast, trophectoderm and primitive endoderm (figure 1). The epiblast develops into the embryo proper, whereas the other two lineages give rise to extraembryonic tissues. The latter not only develop into essential structures such as the placenta to support the development of the embryo but also act as signalling sources to allocate lineages to the epiblast cells. Bone morphogenetic protein (BMP) signalling at embryonic day (E) 6.25 after implantation from the extraembryonic tissue to the proximal epiblast results in the specification of the germ cell lineage, by assigning a few epiblast cells to become PGCs [4,5]. While the remaining epiblast cells initiate differentiation towards somatic cell lineages, nascent PGCs reverse this programme by switching on the expression of a transcriptional network including BLIMP1, PRDM14 and AP2γ [6–8]. These factors drive transcriptional changes and epigenetic remodelling in part by inducing the re-expression of pluripotency genes and repressing the DNA methylation machinery, accompanied by genome-wide DNA demethylation, X chromosome reactivation, erasure of imprints and dynamic changes in histone modification signatures [9–14]. During this reprogramming event, PGCs proliferate and migrate towards the genital ridges, which they colonize by E10.5. Female PGCs enter meiosis at approximately E12.5 to produce oocytes, and male PGCs induce a mitotic arrest at approximately E13.5 before they undergo spermatogenesis.Figure 1.


Primordial germ cell specification: a context-dependent cellular differentiation event [corrected].

Günesdogan U, Magnúsdóttir E, Surani MA - Philos. Trans. R. Soc. Lond., B, Biol. Sci. (2014)

Embryonic origin of PGCs in vivo and PGC derivation in vitro. The preimplantation blastocyst at E4.5 consists of the embryonic lineage, the epiblast, and two extraembryonic lineages, primitive endoderm and trophectoderm. After implantation at E6.5, signalling from the extraembryonic ectoderm as well as from the visceral endoderm induces a few cells of the proximal epiblast to become PGCs. In vitro, ES cells, which are derived from the preimplantation epiblast, can be differentiated into epiblast-like cells (EpiLCs) with Activin A and basic fibroblast growth factor. EpiLCs, in turn, respond to BMP4 to give rise to functional PGC-like cells. Epiblast stem cells (EpiSCs), which are traditionally derived from the postimplantation epiblast, also give rise to PGC-like cells, but at a low frequency. (Online version in colour.)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4216466&req=5

RSTB20130543F1: Embryonic origin of PGCs in vivo and PGC derivation in vitro. The preimplantation blastocyst at E4.5 consists of the embryonic lineage, the epiblast, and two extraembryonic lineages, primitive endoderm and trophectoderm. After implantation at E6.5, signalling from the extraembryonic ectoderm as well as from the visceral endoderm induces a few cells of the proximal epiblast to become PGCs. In vitro, ES cells, which are derived from the preimplantation epiblast, can be differentiated into epiblast-like cells (EpiLCs) with Activin A and basic fibroblast growth factor. EpiLCs, in turn, respond to BMP4 to give rise to functional PGC-like cells. Epiblast stem cells (EpiSCs), which are traditionally derived from the postimplantation epiblast, also give rise to PGC-like cells, but at a low frequency. (Online version in colour.)
Mentions: Mammals specify their PGCs in response to instructive signalling during embryonic development. In mice, the blastocyst differentiates into epiblast, trophectoderm and primitive endoderm (figure 1). The epiblast develops into the embryo proper, whereas the other two lineages give rise to extraembryonic tissues. The latter not only develop into essential structures such as the placenta to support the development of the embryo but also act as signalling sources to allocate lineages to the epiblast cells. Bone morphogenetic protein (BMP) signalling at embryonic day (E) 6.25 after implantation from the extraembryonic tissue to the proximal epiblast results in the specification of the germ cell lineage, by assigning a few epiblast cells to become PGCs [4,5]. While the remaining epiblast cells initiate differentiation towards somatic cell lineages, nascent PGCs reverse this programme by switching on the expression of a transcriptional network including BLIMP1, PRDM14 and AP2γ [6–8]. These factors drive transcriptional changes and epigenetic remodelling in part by inducing the re-expression of pluripotency genes and repressing the DNA methylation machinery, accompanied by genome-wide DNA demethylation, X chromosome reactivation, erasure of imprints and dynamic changes in histone modification signatures [9–14]. During this reprogramming event, PGCs proliferate and migrate towards the genital ridges, which they colonize by E10.5. Female PGCs enter meiosis at approximately E12.5 to produce oocytes, and male PGCs induce a mitotic arrest at approximately E13.5 before they undergo spermatogenesis.Figure 1.

Bottom Line: During embryonic development, the foundation of the germline is laid by the specification of primordial germ cells (PGCs) from the postimplantation epiblast via bone morphogenetic protein (BMP) and WNT signalling.However, an unresolved question is how postimplantation epiblast cells acquire the developmental competence for the PGC fate downstream of BMP/WNT signalling.Here, we discuss recent advances on the specification and reprogramming of PGCs thereby highlighting the concept of enhancer function.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK Department of Physiology, Development and Neuroscience, University of Cambridge, Downing St., Cambridge CB2 3DY, UK Wellcome Trust Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.

ABSTRACT
During embryonic development, the foundation of the germline is laid by the specification of primordial germ cells (PGCs) from the postimplantation epiblast via bone morphogenetic protein (BMP) and WNT signalling. While the majority of epiblast cells undergo differentiation towards somatic cell lineages, PGCs initiate a unique cellular programme driven by the cooperation of the transcription factors BLIMP1, PRDM14 and AP2γ. These factors synergistically suppress the ongoing somatic differentiation and drive the re-expression of pluripotency and germ cell-specific genes accompanied by global epigenetic changes. However, an unresolved question is how postimplantation epiblast cells acquire the developmental competence for the PGC fate downstream of BMP/WNT signalling. One emerging concept is that transcriptional enhancers might play a central role in the establishment of developmental competence and the execution of cell fate determination. Here, we discuss recent advances on the specification and reprogramming of PGCs thereby highlighting the concept of enhancer function.

Show MeSH