423a/b1, T and Eomes regulatory regions are bound by Blimp1 in PGCs at a time when
mRNA transcripts of these targets are reduced (Magnusdottir et al. 2013 ). Since
Blimp1 regulates gene expression in association with the histone modifier Prmt5
(Ancelin et al. 2006 ), and Prmt5 in Drosophila associates with Tudor proteins, a
component of germ plasm proteins (Anne and Mechler 2005 ), it suggests that some
of the Blimp1 functions in mice resemble that of molecules that safeguard unipo-
tency of early PGCs in basal organisms (Hayashi et al. 2007 ; Ancelin et al. 2006 ).
Following lineage restriction after Blimp1 activation, these precursors initiate
germ cell specification by activating Prdm14 and Tcfap2c/AP2g. Prdm14 has been
identified as the first germ cell gene to be expressed in mice. It plays critical roles in
two key processes characterizing the germ cell program, namely, reacquisition of
potential pluripotency and epigenetic reprogramming (Yamaji et al. 2008 ).
Prdm14-KO mice lack mature germ cells due to a major loss of PGC during speci-
fication. Prdm14-KO PGCs also fail to upregulate Sox2 and to erase H3K9me2,
which is consistent with the role of Prdm14 in reestablishing pluripotent gene
expression and initiation of epigenetic reprogramming of PGCs.
Tcfap2c/AP2g is also a critical early PGC gene, causing germ cell loss at E8
when mutated in mouse (Weber et al. 2010 ). Both Prdm14 and AP2g work together
to activate PGC genes nanos3 and dnd1, and cooperate with Blimp1 in repressing
somatic genes and epigenetic modifiers. Indeed, this tripartite network of Blimp1,
Tcfap2c/AP2g, and Prdm14 seems sufficient for mouse PGC specification, as dem-
onstrated by the induction of PGC-like cells without cytokines when they are over-
expressed (Magnusdottir et al. 2013 ).
How well conserved is the role of Blimp1 during germ cell specification in other
mammalian species has not yet been fully elucidated. However a recent report shows
that BLIMP1 is activated in human PGC-like cells (hPGCL) after specification by
SOX17. The results suggest that the role of BLIMP1 is to prevent the somatic differ-
entiation potential of these SOX17 expressing cells (Irie et al. 2015 ). Furthermore,
hPGCL cells arise from precursors expressing high levels of BRACHYURY and low
levels of SOX2, resembling posterior primitive streak derived progenitors. These
observations suggest that human germ cell precursors arise from a population of pos-
terior primitive streak cells that activate BLIMP1 in response to paracrine inductive
signals. Information on whether this mechanism also occurs in vivo is still lacking.
8.6.2 Germ Cell Induction Domains in Early Embryos
BMP4 and BMP8b homozygous mutants are deprived of PGCs, and heterozygous
animals have reduced number of them (Lawson et al. 1999 ; Ying et al. 2000 ). By
E5.5 both molecules are secreted by extraembryonic ectoderm cells, which are in
close contact with proximal epiblast cells (Coucouvanis and Martin 1999 ). BMP2 is
produced a little later, from ~E6.5, by visceral endoderm cells, in an area next to the
proximal epiblast (Coucouvanis and Martin 1999 ). The role of these molecules in
germ cell induction was further demonstrated using isolated mouse epiblasts (Ying
8 Mechanisms of Vertebrate Germ Cell Determination