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From The Department of Otolaryngology, University of Iowa, Iowa City, Iowa.
| Correspondence to: Dr Xinchang Zhou, The Department of Otolaryngology, University of Iowa, 5270 CBRB, Iowa City, IA 52242 (e-mail: xinchang-zhou{at}uiowa.edu). |
| Received for publication September 3, 2009; accepted for publication November 9, 2009. |
The androgen receptor (AR), a member of the nuclear receptor superfamily,
is a ligand-dependent transcription factor involved in regulating expression
of an array of androgen-responsive genes. AR-mediated androgen actions play
the important roles in male and female reproductive development and function.
AR mutations can cause a diverse range of diseases, such as testicular
feminization mutation (Tfm) syndrome, prostate cancer, and Kennedy's disease.
However, because of a lack of genetic models, the molecular mechanisms
involved in the physiological and pathological effects of androgen–AR
function in male and female reproductive health remains largely unknown. To
get a better insight into the molecular working mechanisms of the AR, a global
and several cell-specific conditional knockout mouse models have been
developed. These models are reviewed here, and the phenotypes of the different
cell-specific androgen receptor knockout (ARKO) mice are compared with those
of the global ARKO mice.
Key words: Nuclear receptor, conditional knockout, phenotype
Because male mice lacking a functional AR gene are expected to be similar to Tfm male mice with infertility (Quigley et al, 1995; McPhaul, 1999), a successfully disrupted AR gene, essential for male reproduction, is not passed on to the next generation. Furthermore, because all Tfm model animals are genetically male, it is impossible to generate homozygous females with AR gene mutation genetically (Matsumoto et al, 2003). Therefore, it is impractical to generate an androgen receptor knockout (ARKO) mouse line by either breeding or classical gene KO methods. To generate ARKO mice, a Cre-loxP strategy for conditional KO is necessary. The Cre-loxP system uses the expression of P1 phage Cre to catalyze the excision of DNA located between flanking loxP sites. This strategy differs from the standard targeted disruption procedure in that embryonic stem cells are generated in which the target segment is not disrupted but is flanked by loxP sites (floxed). The targeted gene thus functions normally, and mice can be bred to homozygosity for the targeted locus.
The recent global AR knockout male mice showed Tfm syndrome, exhibiting infertility and female-typical external appearance with a blind-end vagina and a clitoris-like phallus. Testes were located in abdominal or inguinal region, and germ cell development was severely disrupted (Yeh et al, 2002; Matsumoto et al, 2003). The global female ARKO mice displayed subfertility with retarded development of mammary glands (Yeh et al, 2002; Yeh et al, 2003; Hu et al, 2004). These findings further emphasized the AR signaling necessary for male external and internal phenotypes, and female ovary and breast development. Because a gene alteration in the whole body can cause a complex phenotype that makes it difficult to differentiate direct effects in a particular tissue or cell type from those secondary effects arising from a gene change in other cell types, it is necessary to use a Cre-lox strategy in transgenic mice expressing Cre recombinase selectively in specific cells to generate a cell-specific ARKO mouse model in which disruption of AR function is exclusively in a particular cell type. Here, we summarize the generation and phenotypes of both the global and cell-specific AR knockout (AR–/y) in germ cells (G-AR–/y), peritubular myoid cells (PM-AR–/y), Leydig cells (L-AR–/y), Sertoli cells (S-AR–/y), and prostate epithelial cell (PEARKO) mouse models to understand the consequences of AR loss in different cell types.
Generation of Global and Cell-Specific ARKO Mice
To generate global or cell-specific ARKO mice, the C57-B6/129/SvEv
loxP-floxed AR mice were first produced
(Yeh et al, 2002,
Matsumoto et al, 2003) and
then mated with mice expressing Cre recombinase ubiquitously or selectively in
specific cells. Global ARKO mice were generated by mating the floxed AR mice
with the transgenic mice ubiquitously expressing Cre driven by the strong
β-actin (ACTB) promoter (Yeh et al,
2002), human cytomegalovirus (CMV) promoter
(Matsumoto et al, 2003), or
phosphoglycerate kinase (PGK) promoter
(Ophoff et al, 2009). Sertoli
cell–specific ARKO (S-AR–/y) mice were generated by
mating the floxed AR mice with anti-Müllerian hormone (AMH)-Cre
transgenic mice (Chang et al,
2004; De Gendt et al,
2004; Holdcraft and Braun,
2004a). Leydig cell–specific ARKO (L-AR–/y)
mice were generated by mating the floxed AR mice with AMH type II receptor
(AMHRII)–Cre transgenic mice (Xu et
al, 2007). PM cell–specific ARKO (PM-AR–/y)
mice were generated by mating the floxed AR mice with Transgelin-Cre
transgenic mice (Zhang et al,
2006). Germ cell–specific ARKO (G-AR–/y)
mice were generated by mating the floxed AR mice with synaptonemal complex
protein 1 (Sycp1)–Cre transgenic mice
(Tsai et al, 2006). Prostate
epithelial ARKO (PEARKO) mice are produced by Cre recombinase under the
control of the PEARKO–specific probasin gene promoter
(Simanainen et al, 2007;
Niu et al, 2008).
Phenotypes of Global and Cell-Specific ARKO Mice
Phenotypes of Global ARKO Mice—
Phenotypes of the global ARKO male mice. The early differentiation
of male accessory sex organs is dependent on testosterone during early
embryonic development when 5
reductase does not yet exist; the major
effect of testosterone directs the differentiation of male-specific Wolffian
duct–derived internal genital structures at early embryonic stages,
including the epididymis, vas deferens, and seminal vesicles
(Wilson et al, 1981;
Tong et al, 1996;
Hutson et al, 1997). However,
dihydroxytestosterone (DHT)-dependent development of the prostate and
prostatic urethra occurs internally, and the differentiation of genital
structures externalizes at later embryonic developmental stages, when the
5 reductase responsible for conversion of testosterone to DHT is
available (Quigley, 1998). If
the AR fails to activate its target genes in the presence of androgens during
these critical stages, severe defects in male sex differentiation and
phenotype development ensue. Global ARKO males
(Figure 1) were infertile and
had a female-like appearance, including a short genito-anal distance, vagina
with a blind end, and clitoris-like phallus instead of a penis and scrotum.
The vas deferens, epididymis, seminal vesicle, and prostate were all absent in
ARKO males. However, ovaries, fallopian tubes, and uteri were not observed,
although small abdominal or inguinal testes were present, similar to Tfm mice
or humans with complete androgen insensitivity syndrome
(Yeh et al, 2002;
Matsumoto et al, 2003). The
external genitalia in male ARKO mice appeared feminized. The penis seemed
microphallic, and the urethra showed hypospadia. The scrotum was poorly
developed and looked like the labia majora in the female. Histological
examination of the testes showed that spermatogenesis was severely arrested at
pachytene spermatocytes. From these results, it was clear that AR was
essential for the development of male reproductive organs and spermatogenesis,
although it was not required for the formation of testes.
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Phenotypes of Cell-Specific ARKO Mice— Phenotypes of Sertoli cell–selective ARKO mice. Sertoli cells are generally believed to be the primary mediators of androgen regulation of spermatogenesis because they provide physical and nutritional support to developing germ cells (Griswold, 1998). The hypothesis was examined by three Sertoli cell–specific ARKO (S-AR–/y) groups (Chang et al, 2004; De Gendt et al, 2004; Holdcraft and Braun, 2004a). In contrast to global ARKO mice, results from S-AR–/y mice showed a normal external male appearance with normal internal male genital tract development. S-AR–/y males (Figure 3) have fully descended testes, but size is markedly reduced. S-AR–/y testis histologically showed a decrease in diameter of seminiferous tubules and reduced germ cell complement compared with wild-type male littermates. Poor germ cell differentiation, with the majority of germ cell maturation ceasing at the diplotene primary spermatocyte stage, was seen in the seminiferous tubules of S-AR–/y mice (Chang et al, 2004). Occasionally, a few secondary spermatocytes occur, and very few round spermatids exist (De Gendt et al, 2004; Holdcraft and Braun, 2004a), in agreement with earlier studies, in which androgens and AR play an important role in Sertoli cell maturation rather than Sertoli cell proliferation. Some studies (De Gendt et al, 2004; Tan et al, 2005) showed that adult S-AR–/y mice develop nearly normal numbers of Sertoli cells compared with the wild-type male control, indicating that the effect of androgens on the number of Sertoli cells is not mediated by the AR signal pathway. More detailed analysis of the S-AR–/y testes revealed that androgen, acting through the Sertoli cell AR, regulates the microenvironment of the seminiferous epithelium by influencing a broad spectrum of gene changes in Sertoli cells (Denolet et al, 2006; Wang et al, 2006; Eacker et al, 2007). These results showed that loss of Sertoli cell–specific AR function could impair the normal supportive function for movement of developing germ cells, the junction complex formation and basement membrane development of Sertoli cells or the functional integrity of the blood–testis barrier, and Sertoli cell nursery functions for developing germ cells (Denolet et al, 2006; Wang et al, 2006). Surprisingly, development and function of the adult generation of Leydig cells was disturbed not only in ARKO but also in S-AR–/y mice (De Gendt et al, 2005). Leydig cell number in S-AR–/y testis was normal on day 12 but was reduced by more than 40% at later ages, and the Leydig cell size appeared to be increased. However, Leydig cell number in global ARKOs was reduced by up to 83% at all ages, and Leydig cell size did not increase beyond day 12. Immunohistochemistry and quantitative reverse transcriptase polymerase chain reaction for Leydig cell–specific markers confirmed that steroidogenic function per Leydig cell was increased in S-AR–/y mice but decreased in global ARKO mice. The altered Leydig cell number and function in the S-AR–/y testis might be due to expression changes of platelet-derived growth factor-A and estrogen sulfotransferase. The epididymis size in S-AR–/y mice was decreased by 63% of wild-type size (Wang et al, 2006), and S-AR–/y mice failed to impregnate wild-type female mice because of an absence of mature sperm production (Chang et al, 2004; De Gendt et al, 2004; Holdcraft and Braun, 2004a). These S-AR–/y mice studies above (Chang et al, 2004; De Gendt et al, 2004; Holdcraft and Braun, 2004a; Tan et al, 2005; Denolet et al, 2006; Wang et al, 2006; Eacker et al, 2007) clearly demonstrated that AR function in Sertoli cells is essential for the maintenance of fully competent Sertoli cell functions and the appropriate hormone levels to support the completion of meiosis I during spermatogenesis.
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Phenotypes of Leydig cell–selective ARKO mice. Testicular testosterone produced by the Leydig cells is essential for qualitatively and quantitatively complete spermatogenesis and development of the male phenotype. Long-term intratesticular testosterone withdrawal causes the failure of progression of round to elongated spermatids, particularly during stages VII and VIII of the spermatogenic cycle (O'Donnell et al, 1994). The AR is also expressed abundantly in the mature Leydig cells. Knocking out the AR selectively in Leydig cells (L-AR–/y) by Amhr2-driven Cre strategy (Tsai et al, 2006; Xu et al, 2007) resulted in mice with decreased size of testis and epididymis, reduced serum levels of testosterone, and increased serum levels of LH. The histology of adult L-AR–/y mice testes showed a decrease in diameter of seminiferous tubules and germ cell development arrested predominantly at the round spermatid stage. There were no further differentiated mature elongated spermatids or spermatozoa throughout the L-AR–/y testis. Consequently, L-AR–/y mice were infertile because no sperm existed in the epididymis. Compared with wild-type male mice, the decreased size of testis in L-AR–/y mice was mainly because of a defect in Leydig cell steroidogenic function subsequently affecting Sertoli cell functions to support postmeiotic germ cells, whereas the decrease in epididymis size in L-AR–/y mice could be due to the lower serum testosterone levels and no mature sperm production. The decreased synthesis of testosterone by Leydig cells and lower levels of serum testosterone reduced feedback on the hypothalamus and pituitary; thus, LH levels were elevated. It is important to note that the AR knockout in Leydig cells in this model was not complete. S-AR–/y mice also had consequences for the development of normal Leydig cell numbers with a normal or increased Leydig cell size, whereas the size of the Leydig cells in ARKO mice was reduced (De Gendt et al, 2005). The L-AR–/y mice studies revealed that AR function in Leydig cells is essential for the maintenance of appropriate Leydig cell steroidogenic function and the subsequent affect on Sertoli cell functions to support spermiogenesis: the final differentiation of round spermatids to mature elongated spermatids (Xu et al, 2007).
Phenotypes of PM cell–selective ARKO mice. PM cells are the AR-positive cells surrounding the seminiferous tubules in the testis. These cells might play an indirect role in spermatogenesis through control and maintenance of Sertoli cell function, as well as in the transport of spermatozoa through the tubular lumen by contractions of the seminiferous tubules (Maekawa et al, 1996; Romano et al, 2005). Indeed, the adult PM-AR–/y mice exhibited decreased testis size and decreased epididymal sperm count compared with wild-type males, but fertility was normal (Zhang et al, 2006). Loss of functional AR in PM cells might impair smooth muscle contractility, Sertoli cell nourishing function, and the integrity of Sertoli cell junctions, consequently affecting testis sperm production and slowing down germ cell movement (Zhang et al, 2006). However, a recent study on the PM cell–selective ARKO mice (Welsh et al, 2009) showed that all PM-ARKO males were azoospermic and infertile, indicating that AR in PM cells is essential for normal testis function, spermatogenesis, and fertility in males. The very different testicular phenotypes from the two research groups of PM-ARKO mice were just caused by their usage of different smooth muscle–driven Cre lines (SM22-Cre and smMHC-Cre) on cell-specific ablation of testicular AR from mouse testes, because the SM22-Cre line reported by Zhang et al (2006) did not alter AR expression in testicular PM cells (Frutkin et al, 2006, Welsh et al, 2009), whereas the smMHC-Cre line used by Welsh et al (2009) deleted AR from a proportion of PM cells, although both lines deleted AR from smooth muscle cells surrounding testicular blood vessels. Therefore, the mild phenotypes reported by Zhang et al (2006) in their PM cell AR knockout (KO) model might not truly reflect the importance of androgen action via PM cells.
Phenotypes of germ cell–selective ARKO mice. Unlike Sertoli cells, PM cells, and Leydig cells (Anthony et al, 1989; Sar et al, 1990; Kimura et al, 1993; Bremner et al, 1994; Vornberger et al, 1994; Zhou et al, 1996), whether germ cells express the AR by localization of AR with antibodies is still controversial. Some studies indicated that AR is present in germ cells in different species (Kimura et al, 1993; Janssen et al, 1994; Vornberger et al, 1994; Zhou et al, 1996; Arenas et al, 2001), but other reports showed little AR staining in the germ cells (Galena et al, 1974; Grootegoed et al, 1977; Anthony et al, 1989; Bremner et al, 1994; Van Roijen et al, 1995; Suarez-Quian et al, 1999; Pelletier et al, 2000). The testis of G-AR–/y mice showed similar testis size and normal spermatogenesis at every spermatogenic stage compared with wild-type testis (Tsai et al, 2006). The G-AR–/y mice study clearly demonstrated that androgen/AR signals in germ cells do not have significant effects on sperm maturation and testis development.
Phenotypes of prostate epithelial– or prostate stroma–selective ARKO or AR knockdown mice, or both. The prostate is an androgen-dependent organ during fetal organogenesis, through pubertal development when the prostate completes structural and functional maturation, and in later life when prostate cells remain sensitive to androgen during evolution of prostate disease (Cunha et al, 2004; Heinlein and Chang, 2004). Androgens stimulate proliferation and restrain apoptosis of prostate cells. Prostate diseases during later life are among the major causes of death, disability, and health costs in developed countries. Compared with the global ARKO mice exhibiting abolished prostate development, the PEARKO mice (Simanainen et al, 2007, 2009; Niu et al, 2008) showed prostate development with normal branching morphogenesis but lobe-specific decrease in prostate weight and hindered structural and functional differentiation of the mature prostate epithelium. The most striking change was increased proliferation and abnormal lesions of epithelial cells predominantly in the anterior lobe of PEARKO mice. These results indicated the vital role of stromal AR in postnatal prostate growth and structural differentiation and the necessity of epithelial AR in maintaining functional differentiation and proliferation of epithelial cells in a lobe-specific manner (Simanainen et al, 2007). The epithelial apoptosis in castration-induced prostatic involution did not significantly differ between control (intact AR) and PEARKO (only stromal AR) males, demonstrating that prostate epithelial involution after castration is mediated primarily via stromal AR-dependent apoptotic signals. The epithelial AR inactivation during postnatal prostate development sensitizes PEARKOs to paracrine signaling mediated by stromal AR activity, leading to indirect androgen-induced epithelial hyperproliferation and formation of epithelial hyperplastic cysts by aromatizable androgens (Simanainen et al, 2009). The double prostate epithelium AR and stroma AR knockdown mice (Niu et al, 2008) further confirmed that the prostate stromal AR might play a more dominant role than the epithelial AR to promote epithelial proliferation.
Conclusions and Future Directions
The conditional knockout mice are a wonderful tool to use to further
unravel the molecular mechanisms of the roles of the AR gene in male and
female reproduction by global or cell-specific ablations of the AR gene in the
body. From the results of the AR knockout models, we can conclude that
androgen and AR signal pathways in Wolffian ducts, the genital tubercle, and
urogenital sinus during the embryonic developmental stage play a critical role
in the differentiation and development of male internal and external
genitalia, and AR has a role in the structural and functional differentiation
of cells responsible for spermatogenesis, male fertility, and prostate. AR
also has an important role in normal ovary and breast development and function
in females. Activity of the AR plays an important role during at least three
steps of spermatogenesis: progression through meiosis I, the transition from
round to elongated spermatids, and the terminal stages of spermiogenesis
(Holdcraft and Braun, 2004b;
Xu et al, 2007;
Kerkhofs et al, 2009;
Wang et al, 2009). However,
many questions still need to be answered, such as exact molecular mechanisms
for AR regulation of Sertoli cells and Leydig cells, PM cell proliferation and
differentiation, and prostate epithelium and stromal cells. Loss of functional
AR in Sertoli cells has also had marked effects on Leydig cell development and
function by pathways that have been only partially elucidated. It would also
be of interest to determine the loss of AR in which types of cells in the body
would be able to cause agenesis of male accessory genital organs, as in the
global ARKO mice. Future studies include investigation of detailed molecular
mechanisms in cell-specific AR knockout male mice, which possibly results in
creation of a reversibly safe male contraceptive method and improvements in
the treatment of infertility, hypogonadism, and testicular dysgenesis
syndrome, as well as generation of cell-specific ARKO female mice, to explore
the relative contribution of different types of AR-expressed cells to androgen
actions in female folliculogenesis and breast development.
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