Pathways to Pluripotency: How Germ Cells Make Stem Cells - Male Germline Stem Cells Developmental and Regenerative Potential - page 20

also suggested that loss of PTEN did more than just stimulate PGC proliferation,
but in addition had an effect on the differentiation of PGCs (Kimura et al. 2003 ).
One of the key roles of the PTEN protein is to regulate the activity of the AKT
kinase. Indeed, in both PGCs and testicular tumors in Pten flox /+: TNAP/Cre + mice,
high levels of AKT were observed.
In order to further our understanding of the genetic causes of TGCT, Nadeau,
Matin, and colleagues have also utilized chromosome substitution strains (CSS)
(Matin et al. 1999 ). These CSS strains are produced by intercrossing specific inbred
strains of mice and transferring a single full-length chromosome from a donor
strain to a second host strain by repeated backcrossing. Such strains, each carrying
a single full-length chromosome from a donor strain, allow for identification of
genetic loci involved in a specific trait (such as TGCT) via quantitative trait locus
(QTL) analysis. Using such panels Nadeau and colleagues have identified several
chromosomes that influence TGCT incidence in mice including chromosomes
18 and 19 and the Y chromosome (Matin et al. 1999 ; Anderson et al. 2009a, b )
(Fig. 1.4 ). While these studies deserve more attention, in the interests of space they
will not be discussed further here, but without doubt these studies will continue to
contribute to our knowledge of TGCT and the generation of pluripotent stem cells
from PGCs.

1.6 Parallel Pathways to Pluripotency

The ability of PGCs to give rise to pluripotent stem cells in two different situations,
one in vivo and one in vitro , provides a great opportunity in which to compare dif-
ferent routes to the same end. Several pieces of evidence suggest that some of the
molecular mechanisms that play a role in the two processes are shared. The ability
of PGCs to give rise to both experimentally induced teratomas or to EG cells ends
at the time at which they cease proliferation in the embryo at 12.5 dpc, suggesting
that some aspect of PGC differentiation limits both processes. Further, conditional
knockout of the PTEN gene reveals that this gene plays an important role in both
EG derivation and TGCT formation. Future studies aimed at determining whether
the mechanisms regulating EG formation also could affect the incidence of TGCT
could have a significant impact on our understanding of the etiology of testicular
cancer. Conversely, determination of the role of TGCT susceptibility genes in the
process of EG cell formation could reveal important new information about the
control of developmental potency. Ultimately the reward could be a better under-
standing of how normal germ cell development proceeds and why it sometimes
goes wrong.

Acknowledgments I am grateful to Kyle Orwig for the opportunity to write this review and for
his enormous patience, the anonymous reviewers whose comments were so helpful in shaping the
manuscript, and Leendert Looijenga for helpful advice about the origin of human testicular cancer.
I want to also thank the members of my laboratory for their support, especially Robbie Sierra for
commenting on the manuscript and for helping generate the figures. I am especially grateful to