4
germ plasm has been identified that would determine germ cell fate. Mouse PGCs origi-
nate from the epiblast at around embryonic day 6.25 (Ohinata et al. 2005 ). The extraem-
bryonic ectoderm and visceral endoderm produce the signals that instruct a small
number of epiblast cells to become PGCs. Their formation in mice is induced as a result
of bone morphogenetic protein (BMP) signaling. Bmp4 expressed in the extraembry-
onic ectoderm has been shown sufficient to induce PGCs in cultured epiblast. Bmp2 can
do the same with less efficiency, while Bmp8b is also necessary, probably to restrict
inhibitory signals arising from the visceral endoderm (Ohinata et al. 2009 ). Inductive
germ cell specification was also described in urodele amphibians (newts and salaman-
ders). Urodele oocytes lack vegetal pole germ plasm; their PGCs arise in the lateral
plate mesoderm where they form as a result of inductive signals from the ventral endo-
derm (Ikenishi and Nieuwkoop 1978 ). Following induction, Bmp activates the expres-
sion of the transcription factor Blimp1 (Prdm1). Blimp1 plays a critical role in PGC
specification, as it is responsible for the repression of their somatic program (Ohinata
et al. 2005 ). Additional proteins involved in PGC specification are Prdm14, whose role
is to suppress differentiation markers (Tsuneyoshi et al. 2008 ), and Tcfap2c that seems
to function downstream of Blimp1 to suppress mesodermal differentiation (Weber et al.
2010 ). At the same time, a network of pluripotency-associated genes including Oct4,
Sox2, Stella, and Nanog are upregulated in nascent primordial germ cells.
Germ cells rarely become gametes at the location they first emerge. PGCs form
at the perimeter of the embryo proper, and during later development they translocate
to their final residence inside the embryo. Their migration is well characterized in
mammals, where they move from the epiblast to the yolk sac/allantois and then to
the developing hindgut until they finally colonize the genital ridges (Hyldig et al.
2011 ). Avian PGCs use a different path. In the chicken embryo, they move from the
epiblast to the hypoblast and then reach the area known as the germinal crescent.
Subsequently, PGCs enter the blood vessels and use the embryonic circulation for
transport. They exit the circulation in the vicinity of the genital ridges and are drawn
to their final destination by chemotactic attraction (Kuwana et al. 1986 ). Some rep-
tiles utilize a pattern of PGC development similar to that of mice, while in others
PGCs take a route similar to that described in the chicken, i.e., they migrate to the
anterior region equivalent to the germinal crescent and travel to the genital ridges
via the circulation (for a recent review, see Johnson and Alberio 2015 ).
Since the genetic information needs to be carried over to the next generation, the
genome must remain intact during its passage through the germline. Also, the genome
in germ cells must be reset to a basic, totipotent state. This is particularly important in
species that do not contain maternal germ plasm, and PGC specification takes place
later in development. In the mouse, for example, PGC specification is deferred until
after implantation. However, the epiblast adopts somatic epigenetic features rapidly
after implantation: DNA methylation levels of the epiblast in the embryonic day 6.
embryo are more similar to somatic tissues than to the inner cell mass of the blastocyst
(Popp et al. 2010 ). Pluripotency genes such as Oct4 and Nanog, as well as germline-
specific genes, are repressed in the epiblast cells by DNA methylation; this prevents
their activation, which would be detrimental at this point (reviewed by Messerschmidt
et al. 2014 ). Due to these reasons, PGCs must undergo extensive epigenetic
Z. Machaty et al.