Pathways to Pluripotency: How Germ Cells Make Stem Cells - Male Germline Stem Cells Developmental and Regenerative Potential - page 13

in Turner and Grose 2010 ). This molecule then transmits the signal via molecules
such as the serine/threonine kinase AKT. Signaling via this pathway sends anti-
apoptotic signals that allow cells to survive and, with other appropriate signals, to
proliferate. The activity of PI3K is attenuated by the phosphatase and tensin (PTEN)
homolog, which is a phosphatase that dephosphorylates the messenger and therefore
antagonizes the activity of PI3K (see Courtney et al. 2010 for review). Because of
the important role of the PI3K/AKT signaling pathway downstream of many recep-
tor tyrosine kinases, examining the role of AKT in PGC growth and EG develop-
ment is an important goal. Nakano and colleagues produced mice in which they
could conditionally activate AKT in specific lineages. When AKT was activated in
PGCs it dramatically augmented the production of EG cells (Kimura et al. 2008 )
(Fig. 1.3 ). In addition these studies found that activation of AKT in this manner
could partially substitute for FGF-2 (Kimura et al. 2008 ). Interestingly, one of the
actions of AKT signaling might be to suppress p53 activity by stabilizing Mdm2, a
key regulator of the p53 protein. The role of p53 in induction of pluripotency is still
being explored, but these studies perhaps provide a clue as to how FGF signaling
might lead to the formation of pluripotent cells from PGCs.
Other important clues as to the molecular mechanisms that drive cells into the
pluripotent state have come from studies by Yamanaka and colleagues in which
they were able to reprogram fibroblasts into a pluripotent state to create so-called
induced pluripotent stem cells (iPSCs) (Takahashi and Yamanaka 2006 ). These
studies demonstrated that forced expression of four genes in mouse fibroblasts
could convert them into iPSCs. These genes include the POU domain transcription
factor Oct3 (POU5f1), the Sry-HMG-box related factor Sox2, the Kruppel-like
factor Klf4, and the Myc proto-oncogene. Subsequent studies have refined our
knowledge of the factors required for somatic cell reprogramming. Studies on
human cells also identified the Lin28 gene as capable of reprogramming fibroblasts
in conjunction with Oct4, Sox2, and Nanog (Yu et al. 2007 ), and other studies
demonstrated that Myc is not required for iPSC generation (Nakagawa et al. 2008 ).
Exclusion of Myc from the transduction cocktail still allows iPSC generation albeit
at reduced efficiency (Nakagawa et al. 2008 ). Nevertheless, these studies indicate
some of the key pathways required for reprogramming cells to pluripotency and,
therefore, what factors might be involved in reprogramming PGCs to a pluripotent
state. Analysis of EG cell derivation reveals the role that some of these factors play
in this process. Of course PGCs, like ES cells and iPSCs, express Oct4, Sox2, and
Nanog (Scholer et al. 1990 ; Chambers et al. 2003 ; Avilion et al. 2003 ; Yamaji et al.
2008 ) and conditional knockout studies in mice demonstrate that Oct4 and Nanog
have important functions in PGCs (Kehler et al. 2004 ; Yamaguchi et al. 2009 ).
Therefore, converting PGCs into pluripotent cells likely does not require the up-
regulation, or the level of up-regulation, of those factors as it does in the conversion
of fibroblasts or other somatic cells to pluripotency.
Because of the role of Prdm1 in normal germ cell development from pluripotent
cells of the early embryo, an interesting question concerns the role of Prdm1 in the
process of conversion of PGCs back into pluripotent stem cells. It has been suggested
that one role of Prdm1 in normal PGC development is to block reversion of nascent