A Signaling Principle for the Specification of the Germ Cell Lineage in Mice

Abstract

Specification of the germ cell lineage is vital to development and heredity. In mice, the germ cell fate is induced in pluripotent epiblast cells by signaling molecules, yet the underlying mechanism remains unknown. Here we demonstrate that germ cell fate in the epiblast is a direct consequence of Bmp4 signaling from the extraembryonic ectoderm (ExE), which is antagonized by the anterior visceral endoderm (AVE). Strikingly, Bmp8b from the ExE restricts AVE development, thereby contributing to Bmp4 signaling. Furthermore, Wnt3 in the epiblast ensures its responsiveness to Bmp4. Serum-free, defined cultures revealed that, in response to Bmp4, competent epiblast cells uniformly expressed key transcriptional regulators Blimp1 and Prdm14 and acquired germ-cell properties, including genome-wide epigenetic reprogramming, in an orderly fashion. Notably, the induced cells contributed to both spermatogenesis and fertility of offspring. By identifying a signaling principle in germ cell specification, our study establishes a robust strategy for reconstituting the mammalian germ cell lineage in vitro.

In vitro production of fertile sperm from murine spermatogonial stem cell lines

“…In this regard, germ cells or primordial germ cells reported or claimed to have been derived from ES/iPS cells and epiblast cells [34][35][36][37] could be tested regarding their spermatogenic activity with our in vitro system. This particular application of our method would break the boundary between germ and somatic cells, and open a new phase in germ cell research.…”

Parental epigenetic control of embryogenesis: a balance between inheritance and reprogramming?

“…This is not the case in mammals, where primordial germ cells (PGCs) are specified from a small population of posterior proximal epiblast cells (Figure 2) [16], [17]. Prior to undergoing overt cellular differentiation, PGCs undergo changes in gene expression state and DNA and histone methylation levels that are believed to represent reprogramming of these cells [18], [19].…”

The crucial role of Activin A on the formation of primordial germ cell-like cells from skin-derived stem cells in vitro

“…36 It implies that PGCLCs differentiation in vitro needs to undergo dedifferentiation into EpiLCs, and ActA promotes PGCLC formation by promoting this process and enhances the ability of these EpiLCs to response Bmp4 by upregulating Wnt3 level.…”