Pathways to Pluripotency: How Germ Cells Make Stem Cells - Male Germline Stem Cells Developmental and Regenerative Potential - page 19

on chromosome 13 in a region syntenic to a portion of human chromosome 5q that
has been associated with susceptibility to TGCT in humans (Muller et al. 2000 ).
But further information about the pgct1 is so far lacking. Similarly, while mice car-
rying a targeted disruption of the gene encoding the essential RNA component of
the telomerase holoenzyme (mTR) provide evidence for a role for telomerase in the
etiology of TGCT, there is little understanding of how loss of mTR leads to TGCT
(Rudolph et al. 1999 ). Loss of p53 is one of the most common events in human
cancer, and mice lacking p53 develop multiple tumor types but mostly lymphomas
(Harvey et al. 1993 ). However, when the p53 mutation was introduced onto the 129/
SV background, tumors developed more quickly and the spectrum of tumors was
altered. While these mice still developed lymphomas, about half of the 129/Sv p53-
deficient males developed testicular tumors with a phenotype of teratocarcinomas.
By comparison, only about 10% of control animals with a mixed genetic back-
ground developed this type of tumor (Harvey et al. 1993 ). Therefore, loss of p53
increased tumor incidence on the 129/Sv background but also altered the type of
tumor from teratomas to teratocarcinomas. Whether the loss of p53 stimulates
development of testicular tumors or promotes the growth of the tumors once they
have formed is unclear. The recent discovery that down-regulation of p53 can
greatly accelerate the generation of iPSCs from fibroblasts indicates that p53 could
play a role in development of pluripotent EC cells from PGCs (Hanna et al. 2009 ;
Zhao et al. 2008 ). Therefore, further studies on the mechanism by which loss of p53
stimulates the development of TGCT in the 129/Sv strain are clearly warranted.
Another major tumor suppressor is the PTEN gene, which is mutated at high
frequency in a large numbers of human cancers. In order to determine the role of
the PTEN gene in PGCs, Nakano and colleagues carried out targeted deletion of
PTEN in PGCs using both a floxed allele of PTEN and mice expressing the Cre
recombinase from the TNAP gene, which is expressed in PGCs (Kimura et al.
2003 ). These animals allowed deletion of the PTEN gene in PGCs during embryo-
genesis. Examination of Pten flox /+: TNAP/Cre + male mice at birth revealed that,
remarkably, all of the animals had developed bilateral testicular tumors each with
multiple foci. When PGCs were examined in the Pten flox /+: TNAP/Cre + embryos it
was found that they had increased proliferation, exactly the phenotype described by
Stevens in his original description of TGCT in mice (Kimura et al. 2003 ). In wild-
type mice only 3% of PGCs were found to be proliferating at 13.5 dpc. By 15.5 dpc
no proliferating PGCs could be detected. In mice in which PTEN was deleted in
germ cells, the number of proliferating PGCs at 13.5 dpc was similar to that seen
in wildtype embryos. But at the later stages of development, 14.5 and 15.5 dpc, a
significant number of mitotic figures were identified in PTEN-deficient PGCs.
Importantly, these animals develop TGCT. Thus, loss of PTEN causes susceptibility
to TGCT (Fig. 1.4 ). These studies also examined the ability of PGCs in which the
PTEN gene had been floxed to give rise to EG cells in vitro . Such cells were found
to have in increased ability to give rise to EG cells. Thus, loss of PTEN makes
PGCs susceptible to giving rise to pluripotent stem cells both in vivo and in vitro .
These data suggest that at least some of the mechanisms controlling the transition
of PGCs into these two pluripotent states are shared. Interestingly, these studies