Pathways to Pluripotency: How Germ Cells Make Stem Cells - Male Germline Stem Cells Developmental and Regenerative Potential - page 12

Fig. 1.3 Mechanism of growth factor action in the creation of embryonic germ cells from
primordial germ cells. Kit ligand ( KL ) acting through the C-Kit receptor regulates primordial germ
cell survival. Likely, that involves activation of the PI3 Kinase and AKT signaling pathway, which
is counteracted by the activity of PTEN. Leukemia inhibitory factor ( LIF ), acting through the
bipartite receptor comprised of gp130 and the LIF receptor ( LIFR ), also likely sends survival sig-
nals that together with signaling from the C-Kit receptor regulate PGC proliferation. One of the
signaling molecules activated by LIF signaling is the signal transducer and activator of
transcription-3 ( Stat3 ), which in turn can regulate the levels of C-myc. The role of fibroblast growth
factor ( FGF ) signaling in normal germ cell development is less clear. Nevertheless, activation of
the FGF receptor ( FGFR ) in PGCs in culture can also activate AKT as well as leading to down-
regulation of Prdm1 and later translocation of Prmt5 out of the PGC nucleus. These events are
thought to lead to loss of PGC fate in developing PGCs. Together with Stat3-mediated up-regula-
tion of C-myc, activation of the FGF signaling pathway leads to up-regulation of Kruppel-like
factor 4 ( Klf4 ), and transition of PGCs to a pluripotent state. FGF signaling may also have other
effects on chromatin remodeling, which could also contribute to conversion of PGCs to EG cells
generation of EG cells, which raises interesting questions about the mode of action
of FGF2 and the FGF signaling pathway in reprogramming of PGCs to pluripo-
tency (Durcova-Hills et al. 2008 ).
Of course a key question is how signaling pathways such as the FGF pathway, or
those affected by TSA treatment, cause conversion of PGCs into EG cells. One of
the important pathways downstream of FGF receptors is a pathway including the
phosphoinositide-3 kinase (PI3K), which produces the second messenger, phos-
phatidylinositol (3,4,5)-triphosphate (PtdIns(3,4,5) P 3) from PtdIns(4,5) P 2 (reviewed