br Experimental Procedures br Acknowledgments br Introductio

Experimental Procedures
Acknowledgments
Introduction Germ Y27632 are the only cells that continue to be reprogrammed throughout their lifetime in order to transfer genetic information to subsequent generations (Sasaki and Matsui, 2008). Germ cells have unique characteristics such as genome-wide epigenetic reprogramming and the potential to become pluripotent (Saitou and Yamaji, 2012). Primordial germ cells (PGCs) are specified at embryonic day (E) 7 in the epiblast. Blimp-1, Prdm14, and Tfap2c have critical roles in the specification of PGCs. A functional study of knockout embryos showed that BLIMP-1 represses somatic genes (Ohinata et al., 2005), whereas PRDM14 activates germ cell development genes (Yamaji et al., 2008). Tfap2c is thought to be a functional downstream target of BLIMP-1 (Weber et al., 2010). These three factors are sufficient to induce PGCs in vitro (Nakaki et al., 2013). Germ cell development, especially PGC specification, shares similarities with somatic cell reprogramming. Factors involved in germ cell development also function in the reprogramming of somatic cells (Nagamatsu et al., 2011). Moreover, PGCs have the potential to dedifferentiate into pluripotent embryonic germ cells (EGCs) without exogenous gene activation (Matsui et al., 1992). Although pluripotent stem cells and PGCs share many common features, PGCs are unipotent germ lineage-restricted cells and are distinct from pluripotent stem cells. When injected into blastocysts, PGCs do not give rise to any cell lineages (Leitch et al., 2014). Originally, EGCs were established thorough screening of the culture conditions required for PGC proliferation (Matsui et al., 1992). Basic fibroblast growth factor (bFGF), leukemia inhibitory factor (LIF), and membrane-bound stem cell factor (mSCF) are present under these culture conditions. Because activation of phosphoinositide-3-kinase and AKT signaling negates the requirement for bFGF in such cultures, Akt is known to be involved in the induction of pluripotency in PGCs (Kimura et al., 2008). Recently, it was reported that a combination of signaling inhibitors enhances the efficiency of EGC formation (Leitch et al., 2010; Nagamatsu et al., 2012a). These inhibitors consist of 2i inhibitors (inhibitors of mitogen-activated protein kinase kinase [MEK] and glycogen synthase kinase-β), which maintain pluripotency, and A83 (an inhibitor of transforming growth factor-β receptor), which enhances somatic cell reprogramming (Ying et al., 2008; Yuan et al., 2011). However, the mechanisms underlying the induction of pluripotency in PGCs remain largely elusive. While only germ cells can give rise to pluripotent cells following implantation, induced pluripotent stem cell (iPSC) technology enables pluripotent cells to be established from somatic cells (Takahashi and Yamanaka, 2006). Methyl-CpG binding domain protein 3 (Mbd3) was recently identified as a roadblock of somatic cell reprogramming (Rais et al., 2013). MBD3 is a component of the nucleosome remodeling deacetylase (NuRD) complex, which has histone deacetylase activity and serves to close the chromatin structure (Hu and Wade, 2012).
Results
Discussion We have identified that Blimp-1 functions as a gatekeeper of pluripotency in PGCs. Blimp-1 was originally identified as a transcriptional repressor in B cell maturation (Turner et al., 1994). During PGC specification, BLIMP-1 is important for the suppression of somatic cell programming (Kurimoto et al., 2008). The targets of BLIMP-1 may differ according to the situation. Transcription factors change the targets in a cell state-dependent manner. For example, Niwa et al. reported that the targets of SOX2 differed between ESCs and trophoblast stem cells because of different binding partners (Adachi et al., 2013). It is reported that BLIMP-1 binds the histone deacetylases TLE1 and EHMT2 in a context-dependent manner (Bikoff et al., 2009). It would be interesting to analyze the binding partners of BLIMP-1 during the specification of PGCs and induction of EGCs.