Pathways to Pluripotency: How Germ Cells Make Stem Cells - Male Germline Stem Cells Developmental and Regenerative Potential - page 17

KL gene, influence TGCT incidence. The Sl d mutation, which represents an
intragenic deletion that results in production of only a soluble form of the ligand, has
no effect on TGCT incidence. Because the Sl and Sl j alleles are large deletions that
delete more than just the KL gene it was possible that the effect on these mutations
on TGCT was not due to deletion of the KL gene but rather to mutation of another
gene. Subsequent studies utilizing the Sl grizzle-belly ( Sl gb ) allele, which deletes only
the KL gene, demonstrated that indeed the effect of Sl mutations on increased TGCT
incidence is due to loss of the transmembrane form of the KL gene (Heaney et al.
2008 ). These studies also point to a paradoxical aspect of TGCT. Mutations that
affect TGCT incidence can also have a negative impact on germ cell numbers. This
seems counterintuitive since typically tumor development is associated with
increased rather than decreased survival and proliferation of cells.
One of the most interesting modifiers of TGCT incidence is the Te r gene, which
was identified as a spontaneous mutation in the 129/SVJ strain of mice (Stevens
1973 ). Mice carrying the Ter mutation have a dramatically increased incidence of
TGCT by comparison with the background 129SvJ strain (Fig. 1.4 ). Noguchi and
Noguchi ( 1985 ) noted that 94% of Ter/Ter 129SvJ males had teratomas (75% bilateral),
while that number was only 17% in hemizygotes (Noguchi and Noguchi 1985 ).
Cloning of the Ter gene revealed it encodes a mouse ortholog of the zebrafish dead
end ( Dnd ) gene (Youngren et al. 2005 ). The Dnd gene encodes a protein most
closely related to the apobec complementation factor (ACF), which is part of the
editosome that controls the editing of gene transcripts (Matin and Nadeau 2005 ).
It is thought that editing arose as an innate defense against DNA and RNA viruses.
But editing also modulates mRNA stability and translation as well as the occur-
rence of alternative transcripts of nuclear genes. So how might mutations in the Dnd
gene affect the incidence of TGCT? That remains a key question. A number of
transcripts that are known to be edited and include apolipoprotein B, a glutamate
receptor, a cyclooxygenase, and an immunoglobulin, but it has been pointed out
that they seem unlikely to be involved in PGC development or the development of
TGCT (Matin and Nadeau 2005 ). Interestingly, when the Ter mutation is intro-
duced onto other strain backgrounds it does not confer susceptibility to TGCT, but
rather decreases PGC numbers: a phenotype that seems to be a prerequisite for the
development of TGCT. As described above this phenotype of PGC loss is also seen
in Sl mutants, which also increase the susceptibility to TGCT. Interestingly, when
Dnd1 Ter/Ter mutant mice were crossed onto a Bax-null background the loss of PGCs
seen in Dnd1 Ter/Ter mice was partially rescued. Bax, a Bcl-2-associated X protein, is
a pro-apoptotic protein that promotes apoptosis by competing with Bcl-2 itself. The
effect of loss of Bax on PGC death suggests that during normal development Bax
may play a role in PGC loss and may protect animals from testicular tumor forma-
tion on certain genetic backgrounds (Cook et al. 2009 ). These data provide further
support for the link between PGC death and the development of EC cells and
subsequently teratomas. Clearly there is much more to know on that subject.
The most powerful negative modifier of TGCT is the agouti-yellow ( A y ) deletion
since it is the only locus found to decrease the incidence of tumorigenesis in
129Sv/J mice (Noguchi and Stevens 1982 ; Heaney and Nadeau 2008 ) (Fig. 1.4 ).