OTX2 restricts entry to the mouse germline.

Abstract

SummaryThe successful segregation of germ cells from somatic lineages is vital for sexual reproduction and species survival. In the mouse, primordial germ cells (PGCs), precursors of all germ cells, are induced from the post-implantation epiblast1. Induction requires BMP4 signalling to prospective PGCs2 and the intrinsic action of PGC transcription factors (TFs)3–6. However, the molecular mechanisms connecting BMP4 to induction of the PGC TFs responsible for segregating PGCs from somatic lineages are unknown. Here we show that the transcription factor OTX2 is a key regulator of these processes. Down-regulation of Otx2 precedes the initiation of the PGC programme both in vitro and in vivo. Deletion of Otx2 in vitro dramatically increases PGCLC differentiation efficiency and prolongs the period of PGC competence. In the absence of Otx2 activity, PGCLC differentiation becomes independent of the otherwise essential cytokine signals, with germline entry initiating even in the absence of the PGC TF Blimp1. Deletion of Otx2 in vivo increases PGC numbers. These data demonstrate that OTX2 functions repressively upstream of PGC TFs, acting as a roadblock to limit entry of epiblast cells to the germline to a small window in space and time, thereby ensuring correct numerical segregation of germline cells from the soma.