Pathways to Pluripotency: How Germ Cells Make Stem Cells - Male Germline Stem Cells Developmental and Regenerative Potential - page 7

gest that roles for this protein may be to stimulate epigenetic reprogramming events
that occur in germ cells and to up-regulate genes associated with pluripotency such
as Sox2. On the other hand, Prdm14 does not appear to play a major role in the
down-regulation of somatic genes in the forming PGCs (Yamaji et al. 2008 ).
Taken together these studies suggest that the Prdm proteins, Prdm1 and Prdm14,
play a key role in the specification and subsequent development of the germ cell lin-
eage. It has been proposed that Prdm1 may be responsible for repression of the somatic
gene expression program (including Hox genes) in forming germ cells while Prdm14
is responsible for re-acquisition of pluripotency-associated genes and for the genome-
wide epigenetic reprogramming that occurs in germ cells (Yamaji et al. 2008 ).
Once the PGCs have formed, morphogenetic movements of the embryo move
them into the embryo proper so that by 9.5 dpc they lie within the epithelium of
the hindgut (reviewed in Molyneaux and Wylie 2004 ) (Fig. 1.2 ). During the next
few days of development they actively migrate from the hindgut through the
hindgut mesentery towards the dorsal body wall where they colonize the develop-
ing embryonic gonads (Fig. 1.2 ). PGC colonization of the gonads is likely con-
trolled by multiple mechanisms including substrate-mediated adhesion and
chemotactic guidance (Molyneaux and Wylie 2004 ). During migration, interac-
tion of PGCs with the extracellular matrix that comprises the substrate on which
they migrate is likely mediated by multiple heterodimeric integrin receptors,
including a3, a6, av, and b1 (Anderson et al. 1999 ). By 12.5 dpc the vast major-
ity of PGCs have reached the embryonic gonad (Molyneaux and Wylie 2004 ).
This period of germ cell development also sees the beginning of expression of
genes that are unique to the germline such as the mouse vasa homolog, also
known as DEAD box polypeptide 4 (Ddx4) (Fujiwara et al. 1994 ; Toyooka et al.
2000 ; Tanaka et al. 2000 ). During the period of migration into the gonads the
germ cells will proliferate to establish the population of cells that will eventually
form the gametes (Tam and Snow 1981 ). Signaling via the C-Kit receptor plays
a key role in regulating PGC survival during this period. Mutations in C-Kit,
encoded at the mouse W or dominant white spotting locus, result in reduction in
number or complete loss of PGGs (see Besmer et al. 1993 for review). Once
PGCs have colonized the gonad they undergo mitotic arrest at 13.5 dpc while
female germ cells enter directly into meiosis in the embryonic gonad (Wylie
1999 ; De 2000 ; McLaren 2003 ).

1.3 How It All Goes Wrong

This normal progression of development goes awry when germ cells continue to
proliferate in the developing gonad. In this situation small nests of proliferating
PGCs are observed in the developing gonad at 15.5 dpc when the remainder of the germ
cells have entered mitotic arrest (Stevens 1967b ) (Fig. 1.2 ). These proliferating germ
cells, now termed embryonal carcinoma (EC) cells, can differentiate and give rise
to benign tumors termed teratomas, which first manifest themselves in the adult testis.