Biomedical Engineering Reference
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and oogenesis helix-loop-helix 1
(
Sohlh1
) have been investigated for roles in sper-
matogenesis (Yoshida et al.
2004
; Ballow et al.
2006
).
7.3.4.1
NGN3
One of the genes suppressed by GDNF exposure in cultured mouse SSCs is
Ngn3
, a
class B bHLH transcription factor, also expressed by multiple types of germ cells in
the mouse germline including A
s
, A
pr
, and A
al
spermatogonia as well as differentiating
spermatogonia (Yoshida et al.
2004, 2006
). While NGN3 expression has been char-
acterized in detail and utilized for tracing SSC and A
pr
/A
al
spermatogonial activity
in vivo
, its role in regulating SSC fate decision has not been examined.
Ngn3
gene
expression dramatically increases in cultured mouse SSCs upon removal of GDNF
stimulation (Oatley et al.
2006
) suggesting a role in SSC differentiation.
7.3.4.2
SOHLH1
In the mouse, expression of SOHLH1 is localized to the proliferating spermatogo-
nial population, similar to NGN3 (Ballow et al.
2006
). SOHLH1 is also a class B
bHLH transcription factor believed to have a role in cellular differentiation (Ballow
et al.
2006
). In the male germline, expression of SOHLH1 is first observed by
PGCs at embryonic day 15.5 (Ballow et al.
2006
), and similar to PLZF, is not
detected at birth with expression being exclusively localized to proliferating sper-
matogonia in both pre-pubertal and adult mouse testes (Ballow et al.
2006
).
Disruption of
Sohlh1
expression in mice causes infertility due to impaired forma-
tion of spermatocytes, indicating a role in spermatogonial differentiation (Ballow
et al.
2006
). Additionally, NGN3 expression is reduced in SOHLH1 deficient germ
cells, suggesting a connection between these two transcription factors in regulating
spermatogonial differentiation (Ballow et al.
2006
). Because both NGN3 and
SOHLH1 are expressed by A
pr
and A
al
spermatogonia it is possible they have roles
in SSC differentiation but this has yet to be explored in detail.
7.4
GDNF-Activated Signaling Pathways
in Cultured Mouse SSCs
GDNF binds to a heterodimeric receptor complex composed of a GFRa1 and the
tyrosine kinase transmembrane molecule c-RET. Binding of GDNF causes trans-
phosphorylation of specific tyrosine residues in the kinase domain of c-RET, which
subsequently activates down-stream intercellular signaling cascades (Airaksinen
and Saarma
2002
). In neurons, GDNF stimulation activates the mitogen-activated
protein kinase (MAPK) and PI3K/AKT pathways (Kaplan and Miller
2000
;
Airaksinen and Saarma
2002
). Exposure of cultured SSCs to GDNF results in
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