Pathways to Pluripotency: How Germ Cells Make Stem Cells - Male Germline Stem Cells Developmental and Regenerative Potential - page 18

The A y mutation induces the ectopic expression of agouti as well as deleting the
Raly and Eif2s2 genes. All of these changes could affect the incidence of TGCT.
But genetic studies in which the agouti gene product was expressed ectopically in
mice and others in which the expression of Raly was reduced in mice had no effect
on TGCT incidence, suggesting that the Eif2s2 gene was responsible for the
decreased incidence of TGCT in A y mice (Heaney et al. 2009 ). Indeed deletion of
the Eif2s2 , which encodes the beta subunit of the translation initiation factor eIF2,
caused a twofold decrease in TGCT incidence in mice (Heaney et al. 2009 ).
Interestingly it was found that reduced expression of Eif2s2 decreased the number
of aberrantly proliferating PGCs in susceptible embryos at 16.5 dpc, suggesting
that this could be one mechanism by which the Eif2s2 gene could influence TGCT
incidence (Heaney et al. 2009 ). Yet reduction in Eif2s2 also was associated with
impaired spermatogenesis, implying that some aspect of germ cell differentiation
may also be affected (Heaney et al. 2009 ). How could loss of Eif2s2 influence
TGCT incidence? The Eif2s2 protein plays a role in regulating translation effi-
ciency, a process that has been associated with tumorigenesis. It has long been
noted that several oncogenes and cell cycle regulators (such as Myc, p27, and
Cyclin D) have complex 5¢-UTR structures. Consequently, in order to maintain the
expression of such genes, cells require highly efficient translation machinery, which
in turn can also suppress apoptosis. It has been proposed in other systems that
increased translation rates might promote tumor progression by supporting prolif-
eration, suppressing apoptosis, and promoting pluripotency (reviewed in Heaney
et al. 2009 ). Heaney et al. suggest a mechanism by which loss of Eif2s2 could nega-
tively influence TGCT formation. They propose the proliferation and differentia-
tion events involved in germ cell development and the derivation of EC cells from
PGCs could be sensitive to gene dosage. Therefore, reduced availability of Eif2s2
could attenuate the ability of aberrantly dividing PGCs to attain the self-renewal
capacity or pluripotency required to transit to a pluripotent stem cell state (Heaney
et al. 2009 ). This intriguing idea about the role of translation in generating pluripo-
tent stem cells is also supported by the identification of the Ter locus as encoding
Dnd , a gene with homology to a component of the RNA editing complex
(see above). The Dnd protein blocks microRNA (miRNA) access to 3¢-UTRs of
transcripts involved in both PGC development such as Nanos1 and in cell cycle
progression such as Cdkn1b. Piwi or Argonaute proteins associated with miRNAs
in the RNA-induced silencing complex (miRISC) bind to 3¢-UTRs or target tran-
scripts. This complex inhibits translation by binding to the 5¢ cap of mRNAs and
blocking assembly of the cap-binding complex. Thus, the proposed roles of Dnd
and Eif2s2 suggest that the regulation of translation by regulation of the 3¢-UTR
and 5¢ cap of mRNAs is important in PGC development and the progression to the
pluripotent state. This idea is confirmed to some extent by the observation that Dnd
and Eif2s2 interact to modulate the incidence of TGCT (Lam et al. 2007 ).
Several other genes or genetic loci have been identified as modifiers of TGCT,
including the tumor suppressors p53 (Harvey et al. 1993 ) and PTEN ( p hosphatase
and t ensin homolog) (Kimura et al. 2003 ), as well as the pgct1 locus (Muller et al.
2000 ) and telomerase (Rudolph et al. 1999 ) (Fig. 1.4 ). The pgct1 locus is located