Segregation of the mouse germline and soma

Abstract

Mouse primordial germ cells (PGCs), originate from the early post-implantation epiblast in response to BMP4 secreted by the extraembryonic ectoderm. However, how BMP4 acts here has remained unclear. Recent work has identified the transcription factor (TF), OTX2 as a key determinant of the segregation of the germline from the soma. OTX2 is expressed ubiquitously in the early post-implantation epiblast, decreasing rapidly in cells that initiate the PGC programme. Otx2 mRNA is also rapidly repressed by BMP4 in vitro, in germline competent cells. Supporting a model in which BMP4 represses Otx2, enforcing sustained OTX2 expression in competent cells blocks germline entry. In contrast, Otx2-null epiblast cells enter the germline with increased efficiency in vitro and in vivo and can do so independently of BMP4. Also, Otx2-null cells can initiate germline entry even without the crucial PGC TF, BLIMP1. In this review, we survey recent advances and propose hypotheses concerning germline entry.

Keywords: NANOG; OTX2; Primordial germ cell; formative pluripotency; germline competent; transcription factors.

Figure 1.

OTX2 acts like a traffic warden to restrict the entry of cells to the germline and usher them instead toward primed pluripotency and ultimately to a somatic fate.

Figure 2.

The underlying molecular events for PGC specification. Activating interactions are indicated by arrows and repressive interactions by blunt arrows. Putative relationships that remain to be fully established during the early events in germline specification are indicated by broken lines.

Figure 3.

Pluripotency gene regulatory network changes during PGC differentiation. The central TFs of the pluripotency gene regulatory network in distinct cell states are indicated by double-headed arrows. During transition from ESCs to EpiLCs NANOG is extinguished and OTX2 is expressed. Upon transition from EpiLCs to PGCLCs OTX2 is extinguished and NANOG is re-expressed. The broken line connecting ESCs to PGCLCs indicates the hypothetical possibility that ESCs may transit to PGCLCs without going through an EpiLC state.

Figure 4.

Distinctions between gene regulatory networks in ESCs and PGCs. Both cell types express OCT4, SOX2 and NANOG. While ESCs also express PRDM14, they do not express the PGC TFs BLIMP1 and AP2γ. The precise nature of the connection between the OCT4, SOX2, NANOG network and the PGC network in PGCs remains to be fully established. A key unresolved question is why ESCs do not express all the PGC network components.