Biomedical Engineering Reference
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is restricted to proliferating spermatogonia including A
s
, A
pr
, and A
al
spermatogonia
(Buaas et al.
2004
; Costoya et al.
2004
). Disruption of PLZF expression in male
mice causes impaired spermatogenesis leading to infertility (Buaas et al.
2004
;
Costoya et al.
2004
). Testes of adult
Plzf
−/−
mice are reduced in size; yet, testis
morphogenesis and germline development during embryogenesis are normal
(Costoya et al.
2004
). Postnatally, development of the seminiferous epithelium is
grossly normal in
Plzf
−/−
mice and several rounds of spermatogenesis occur without
disruption (Buaas et al.
2004
; Costoya et al.
2004
). However, the appearance of
seminiferous tubules with a Sertoli-cell-only phenotype gradually increases with
age in
Plzf
−/−
mice, suggesting a defect in SSC functions to supply the next genera-
tion of germ cell cohorts. Additionally, germ cells from
Plzf
−/−
donor male mice
showed reduced ability to restore spermatogenesis in testes of wild-type recipient
mice upon transplantation, further indicating SSC malfunction due to lack of PLZF
expression (Costoya et al.
2004
).
In vivo
, studies with mutant mice suggest that PLZF has a role in SSC function;
however, whether this regulation is at the level of self-renewal, differentiation, or
survival has not been elucidated. As discussed previously, distinguishing between
these SSC fate decisions by
in vivo
experimentation is challenging. Formation of
Sertoli-cell-only phenotype and inability to reestablish spermatogenesis after trans-
plantation could occur if SSC self-renewal, differentiation, or survival is disrupted.
Also, impaired transition of A
al
spermatogonia into differentiating A
1
spermatogonia
would cause a phenotype similar to Sertoli-cell-only. This disruption could also
lead to seminiferous tubules with Sertoli-cell-only phenotype as a secondary
response of Sertoli cells to cease function or phagocytize germ cells, a response that
would become more pronounced with age.
An additional means of evaluating SSC function is to explore activity in
culture systems that support their self-renewing proliferation for extended periods
of time. Currently, the effects of experimentally manipulating
Plzf
expression on
SSC self-renewal
in vitro
have not been reported. Additionally, expression of
Plzf
is not regulated by GDNF in cultured mouse SSCs (Oatley et al.
2006, 2007
).
Recently, studies suggest that PLZF acts as repressor of c-KIT receptor expres-
sion in male germ cells (Filipponi et al.
2007
). KIT ligand (also termed stem cell
factor) binds the c-KIT receptor and is important for PGC development during
embryonic gonad formation and spermatogenesis in the adult mouse. Expression
of c-KIT is essential for development of differentiating spermatogonia and
becomes apparent in A
al
spermatogonia as they transition into A
1
spermatogonia
(Tajima et al.
1994
; Ohta et al.
2000, 2003
). In the mouse, SSCs do not express
c-KIT (Shinohara et al.
1999
; Kubota et al.
2003
) and exposure to KIT ligand
does not influence SSC self-renewal (Kubota et al.
2004a, b
). Additionally, self-
renewal and differentiation of mouse SSCs in to A
pr
/A
al
spermatogonia occurs
independent of KIT ligand stimulation (Ohta et al.
2003
). Thus, acquiring c-KIT
expression is a function of A
al
spermatogonia that is necessary for transition into
A
1
spermatogonia. The observation that PLZF represses c-KIT expression
suggests a role in preventing the differentiation of A
s
, A
pr
, and A
al
spermatogonia,
not just SSCs.
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