Biomedical Engineering Reference
In-Depth Information
7.3.2.2
ETV5
ETS transcription factors bind conserved N-box sequences within promoter regions
to activate expression of specific genes important for a variety of developmental
processes (Seth et al.
1992
). The Pea3 subfamily of ETS transcription factors
consists of three members including ER81, PEA3, and ETV5 (also termed ERM).
Expression of ETV5 is localized to several tissues including brain, lung, and testis
(Chotteau-Lelievre et al.
1997
). In cultured mouse SSCs,
Etv5
gene expression is
up-regulated upon exposure to GDNF and reducing expression by siRNA treatment
impairs SSC maintenance
in vitro
over one self-renewal cycle (Oatley et al.
2006,
2007
). In the mouse testis, ETV5 expression is localized to both germ cells (Oatley
et al.
2007
) and Sertoli cells (Chen et al.
2005
). In the germ cell population expres-
sion was observed in most spermatogonial subtypes including both proliferating
spermatogonia (i.e., A
s
, A
pr
, and A
al
) and differentiating spermatogonia (Oatley
et al.
2007
). Targeted disruption of
Etv5
in mice causes male infertility, including
progressive development of a Sertoli-cell-only phenotype (Chen et al.
2005
). This
condition is marked by complete loss of germ cells, presumably as an indirect effect
from failure of SSCs to provide new cohorts of developing germ cells. Aging-
related increase of seminiferous tubules with Sertoli-cell-only phenotype occurs in
Etv5
−/−
mice, culminating in complete infertility by 10 weeks of age (Chen et al.
2005
). However, several waves of spermatogenesis occur during early life, indicating
that the progressive formation of seminiferous tubules with Sertoli-cell-only
phenotype is due to impaired SSC self-renewal (Chen et al.
2005
). Additionally,
artificial insemination of wild-type females with sperm from young
Etv5
−/−
males
fail to produce offspring or fertilize wild-type oocytes
in vitro
, suggesting defects
in sperm quality (Schlesser et al.
2008
). Importantly, germ cells from
Etv5
−/−
fail to
generate colonies of spermatogenesis following transplantation into seminiferous
tubules of recipient mice indicating impaired function of SSCs (Tyagi et al.
2009
).
The role of ETV5 in spermatogenesis appears to be complex as expression is
important for function of both Sertoli cells and several germ cell types including
SSCs. However, this function is yet to be fully defined.
7.3.2.3
LHX1
Lim homeobox protein 1 (LHX1, also referred to as LIM1) is a transcription factor
essential for anatomical morphogenesis in the mouse (Shawlot and Behringer
1995
). Disruption of
Lhx1
expression during embryogenesis impairs formation of
the anterior head structure, though the remaining body axis develops normally
(Shawlot and Behringer
1995
). Most
Lhx1
−/−
embryos die at 10 days of embryonic
development; however, a few pups are born dead, appearing normal except head
development is essentially absent. Upon necropsy, LHX1 deficient neonates also
lack kidneys and gonads, suggesting a role in morphogenesis of the urogenital
system (Shawlot and Behringer
1995
). In cultures of wild-type mouse SSCs,
Lhx1
gene expression is up-regulated by GDNF stimulation and reduction of
Lhx1
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