Primordial germ cells (i.e. the precursors of eggs and sperm) are established very early in the development of many multicellular organisms; reasons for this are unknown. This process of establishing the germline involves both: [a] preventing a nonreproductive-cell (somatic-cell) fate; and [b] activating a cellular state known as pluripotency — the ability to give rise to the many different cell types in the body. Understanding germline formation has focused mainly on identifying proteins that specify germline fate, but comparatively little is known about why somatic cells do not acquire such a fate.
In many animals, specification of the germline operates like a hereditary hierarchy in which the passage of molecular components in the cytoplasm will determine which cells will form primordial germ cells. However, some animals –– including salamanders, crickets, mice and perhaps humans –– take a different approach. In the early mouse embryo, designation of the germline occurs as a result of cells “simply being in the right place at the right time”, rather than inheriting the species’ hereditary hierarchy. In this inductive fate-determination scenario, cells of a cylindrically-shaped region, among the pluripotent cells, known as the epiblast, are coaxed into adopting a primordial-germ-cell fate, which is regulated by signals derived from supporting extra-embryonic tissues (cells next to, but not part of, the embryo).
In the mouse, the induction of primordial germ cells from the post-implantation epiblast requires BMP4-signaling to occurr in “prospective” primordial germ cells, combined with the intrinsic action of primordial-germ-cell transcription factors. Authors [see attached article] show that the formation of primordial germ cells in mice can be blocked by a protein called OTX2 (orthodenticle homeobox-2). Down-regulation of the mouse Otx2 gene precedes initiation of the primordial-germ-cell program –– both in cultured cells as well as in the intact animal. Deletion of Otx2 in cultured cells markedly increases the efficiency of primordial-germ-cell-like cell differentiation and prolongs the period of primordial-germ-cell competence.
In the absence of Otx2 activity, differentiation of primordial-germ-like cells becomes independent of the (otherwise essential) cytokine signals; in this case, germline entry is initiated, even in the absence of the primordial-germ-cell transcription factor BLIMP1. Deletion of the Otx2 gene in the animal increases primordial-germ-cell numbers. These findings indicate that OTX2 functions as a repressor –– upstream of primordial-germ-cell transcription factors, acting as a roadblock to limit “entry of epiblast cells to the germline” –– to a small window in space and time, thereby ensuring that only a small number of germline cells separate from the somatic cells of the early embryo.
Nature 25 Oct 2o18; 562: 595–599 [article] and 497–498 (editorial)