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,
From the * Department of Experimental Radiation
Oncology, University of Texas M. D. Anderson Cancer Center, Houston, Texas;
the Laboratory for Experimental Medicine and
Endocrinology, Catholic University of Leuven, Leuven, Belgium; and the
Department of Genome Sciences, University of
Washington School of Medicine, Seattle, Washington.
Present address: The Jackson Laboratory,
Bar Harbor, ME.
| Correspondence to: Gensheng Wang, Department of Experimental Radiation Oncology, Unit 66, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: genwang{at}mdanderson.org). |
| Received for publication September 19, 2008; accepted for publication January 5, 2009. |
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Abstract |
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Key words: Testis, spermatogonial differentiation, juvenile spermatogonial depletion, azoospermia, vinculin
Previous studies (Matsumiya et al, 1999; Tohda et al, 2001) have demonstrated that suppression of testosterone by gonadotropin-releasing hormone (GnRH) analogues reverses the block of spermatogonial differentiation and consequently stimulates the recovery of spermatogenesis to the spermatocyte or early spermatid stage in jsd mice. Further studies (Shetty et al, 2001, 2006) suggested that relatively high testosterone levels are required to maintain the arrest of spermatogonial differentiation in jsd mice and proved that the testosterone action is mediated by the androgen receptor (AR).
In the wild-type mouse testis, AR is localized to the somatic cells, including Sertoli, Leydig, peritubular myoid, and blood vessel smooth muscle, but is not expressed in germ cells (Zhou et al, 2002). The AR expression pattern in jsd mice has been shown to be the same as in wild-type testis (Meistrich et al, 2005). Thus, despite the fact that the primary defect in the jsd mice is in the germ cells, the action of testosterone in maintaining the block of spermatogonial differentiation in jsd mice would be mediated by AR in one or more types of somatic cells. The inhibition of spermatogonial differentiation by testosterone in irradiated rats (Kangasniemi et al, 1996) has also been shown to be attributable to damage to the somatic environment in the testis (Zhang et al, 2007). Recognition of the target cell responsible for the arrest of spermatogonial differentiation in jsd mice will be of importance in elucidation of the mechanism by which hormones mediate this arrest. In addition, the results may be applicable to reversal of toxicant-induced blocks in spermatogonial differentiation in rats, as well as for treatment of human oligospermia/azoospermia, because transient suppression of intratesticular testosterone levels has been reported to facilitate sperm count recovery in humans (Charny and Gordon, 1978).
Androgens and AR are absolutely essential for maintenance of spermatogenesis in normal testes. Global loss of functional AR leads to a testicular feminized phenotype (Lyon and Hawkes, 1970). In order to determine the relative roles of AR in different cell types in testis, it was necessary to develop cell-specific AR knockout mice. When Ar was ablated in Sertoli cells, germ cell development stopped at the spermatocyte (Chang et al, 2004; De Gendt et al, 2004) or early spermatid (Holdcraft and Braun, 2004) stages, suggesting that the AR in the Sertoli cells plays a critical role in maintaining the Sertoli cell's ability to support normal spermatogenesis. In contrast, deletion of Ar in peritubular cells had only small quantitative effects on spermatogenesis (Zhang et al, 2006) and germ cell Ar deletion had no effect on germ cell development (Tsai et al, 2006). Although the deletion of Ar in Leydig cells stopped germ cell development at the round spermatid stage (Xu et al, 2007), this effect of absence of AR in Leydig cells may be only a result of the low testosterone levels and not a result of absence of other Leydig cell androgen-dependent factors. Thus, the Sertoli cell appears to be the primary testicular cell that mediates androgen support of normal spermatogenesis.
In order to determine whether AR in Sertoli cells is also the target for testosterone inhibition of spermatogonial differentiation in jsd mice, we eliminated AR selectively in Sertoli cells (Sertoli cell AR knockout [SCARKO]) in jsd mouse testis by using a Cre-lox conditional knockout strategy (De Gendt et al, 2004; Holdcraft and Braun, 2004). There was no recovery of spermatogenesis in jsd mice lacking AR in their Sertoli cells, demonstrating that the Sertoli cell is not the target cell that mediates the androgen-dependent block of spermatogonial differentiation. In addition, we noted several abnormalities in Sertoli cells of SCARKO-jsd mice, particularly in the positioning of their nuclei, which were much more dramatic than those observed in either SCARKO or jsd mice.
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Materials and Methods |
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Hormone and Hormone Antagonist Treatment
The hormone and hormone analogues were given as previously described
(Shetty et al, 2006). Briefly,
the GnRH antagonist acyline (obtained from the Contraceptive Development
Branch of NICHD, North Bethesda, Maryland) was subcutaneously injected twice,
at doses of 20 and 10 mg/kg body weight at 8 and 10 weeks of age,
respectively, and the mice were killed at 12 weeks of age. For treatment with
flutamide (an AR antagonist) or testosterone, two 2-cm Silastic capsules (Dow
Corning, Midland, Michigan) filled with flutamide (Sigma, St Louis, Missouri)
or one 2-cm capsule filled with testosterone (Sigma) was implanted
subcutaneously at 8 weeks of age and left in place until the mice were killed
4 weeks later.
Testicular Histology
After the mice were killed, testes were removed and fixed in Bouin solution
and embedded in methacrylate. The blocks were sectioned and stained either
with hematoxylin only or with hematoxylin and periodic acid–Schiff
reagent.
The recovery of spermatogenesis was evaluated by the tubule differentiation index (TDI) as previously described (Shetty et al, 2001). The TDI is defined as the percentage of tubules that contain 3 or more differentiating germ cells at the B spermatogonial stage or beyond.
For scoring the abnormal Sertoli cell nuclear organization, the tubules were placed into 1 of 4 categories: tubules with all the Sertoli cell nuclei aligned along the basement membrane (normal tubules); tubules with a few (fewer than 5) Sertoli cell nuclei displaced from the basement membrane; tubules with 5 or more randomly positioned Sertoli cell nuclei displaced from the basement membrane; and tubules with a cluster containing at least 5 (usually degenerating) Sertoli cell nuclei.
Immunostaining and Confocal Microscopy
Testes were removed and fixed in 4% paraformaldehyde for up to 24 hours.
The fixed tissues were embedded in paraffin and sectioned, and the sections
were deparaffinized and subjected to antigen retrieval.
Sections were sequentially incubated with AR antibody (PG21; Prins et al, 1991) at a 1:200 dilution overnight at 4°C, with biotinylated anti-rabbit IgG, and then with an avidin-biotin-peroxidase complex reagent (Vectastain Elite kit; Vector Laboratories, Burlingame, California). The staining was developed by incubation with the peroxidase substrate diaminobenzidine (Vector). The slides were counterstained with hematoxylin.
For immunofluorescent staining of vinculin and vimentin, the sections were incubated with monoclonal mouse anti-human antibodies either to vimentin (1:200 dilution) or to vinculin (1:300 dilution; Sigma) overnight at 4°C. After washing in phosphate-buffered saline, the slides were then incubated with Alexa Fluor 594-conjugated goat anti-mouse antiserum (IgM, 1:200; Molecular Probes, Carlsbad, California) for vimentin or Alexa Fluor 488-conjugated goat anti-mouse (IgG, 1:200; Molecular Probes) for vinculin. The testis sections were examined using a confocal microscopy system (LSM 510; Carl Zeiss, Oberkochen, Germany).
Real-Time Reverse Transcription–PCR
Testis samples were collected from jsd and SCARKO-jsd
mice (n = 4 for each group) and total RNA was extracted using an RNeasy Mini
kit (Qiagen, Valencia, California), with DNase I treatment to digest genomic
DNA. The cDNA was generated with a Transcriptor First Strand cDNA Synthesis
Kit (Roche Applied Sciences, Indianapolis, Indiana). Quantitative real-time
PCR of the cDNA was performed using the Rotor-Gene 3000 thermocycler (Corbett
Research, Sydney, Australia) and SYBR Green (JumpStart Taq Ready Mix; Sigma)
detection to determine the differential expression of the Rhox5 gene.
The housekeeping gene beta-actin was used to normalize concentration values
for each sample. The following primers were used: Rhox5, forward
5'-ggcccaagctcagaatc-3, reverse
5'-ctgaataggatcaatgatgaag-3'; beta actin, forward
5'-tgacaggatgcagaaggagat-3', reverse
5'-tactcctgcttgctgatccac-3'. All samples were run in
triplicate.
Electron Microscopy
Tissues were prepared as described previously
(Chiarini-Garcia and Russell,
2001). Briefly, whole-body perfusion of mice was performed through
the right atrium with 5% glutaraldehyde in 0.05 M cacodylate buffer for
15–20 minutes. Collected testes were fixed in glutaraldehyde overnight,
and then stored in cacodylate buffer. After overnight postfixation with 1%
buffered osmium tetroxide and 1.25% potassium ferrocyanide, samples were
dehydrated and embedded in Araldite 502 medium. Ultrathin sections were cut
and stained with uranyl acetate and lead citrate and examined by transmission
electron microscopy.
Statistics
All quantitative data were represented as arithmetic means ± SEM.
Analysis of variance and subsequent Student-Newman-Keuls post hoc analysis for
pairwise comparisons (Tables 1
and 2), and, for disruption of
Sertoli cell nuclear localization data, independent-samples t tests
were performed to determine the significance of differences (P <
.05) between groups using the SPSS statistical software package (version 12.0;
SPSS Inc, Chicago, Illinois).
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Results |
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To determine whether AR was selectively ablated in Sertoli cells in SCARKO-jsd mice, we examined testicular AR expression by immunohistochemical staining and compared it with that in wild-type, jsd, and SCARKO littermates. In wild-type and jsd mice (Figure 1A and C), AR was detected in Sertoli cells, myoid peritubular cells, vascular smooth muscle cells, and Leydig cells. In SCARKO and SCARKO-jsd mice (Figure 1B and D), although AR staining was still positive in the other testicular somatic cells, AR expression was eliminated in 99.5% of Sertoli cells of SCARKO-jsd mice.
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Spermatogonial Differentiation in SCARKO-jsd Mice
If AR in Sertoli cells mediated the effect of testosterone on inhibition of
spermatogonial differentiation in jsd mice, selective ablation of AR
in Sertoli cells of jsd mice should reverse this inhibition. On other
hand, if AR in Sertoli cells is not the mediator, spermatogonial
differentiation should be blocked in SCARKO-jsd mice to the same
extent as in jsd mice. The testes of SCARKO-jsd mice
(Figure 2B) contained type A
spermatogonia, but almost no type B spermatogonia or spermatocytes, showing
that, without AR in Sertoli cells, spermatogonial differentiation remained
blocked.
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To obtain a semiquantitative analysis of this phenomenon, we scored tubules
as to whether they had fewer than 5 Sertoli nuclei not on basement membrane,
more than 5 Sertoli nuclei not on basement membrane, or clusters of Sertoli
cells (Figure 3). There were
significantly more tubules with 
5 Sertoli cell nuclei detached from the
basement membrane and with Sertoli cell clusters in SCARKO-jsd mice
than in SCARKO mice or in jsd mice. Whereas 44% of tubules in
jsd mice had all Sertoli cells arranged along the basement membrane,
only 1% of tubules in SCARKO-jsd mice had normal Sertoli cell nuclear
localization.
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We next examined the morphology of these Sertoli cell nuclei by electron microscopy. There was a slight but consistent increase in the amount of heterochromatin associated with the nuclear membrane of Sertoli cells at the basement membrane in both SCARKO and SCARKO-jsd mice (Figure 4B and D), compared with those found in wild-type and jsd mice (Figure 4A and C). Such an increased level of heterochromatin is typical of immature, prepubertal Sertoli cells (Solari and Fritz, 1978) and of Sertoli cells whose maturation is prevented by androgen deprivation (Chemes et al, 1979). Meanwhile, the displaced Sertoli cell nuclei, in both jsd and SCARKO-jsd mice, were highly abnormal, characterized by more prominent condensed chromatin deposits on nuclear membrane and irregular shapes (Figure 4E and F). The abnormal chromatin distribution on nuclear membrane was more severe in clustered Sertoli cells than in the scattered Sertoli cells displaced from the basement membrane.
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In order to determine whether the ectoplasmic specialization (ES) junctional complexes between Sertoli cells were affected in SCARKO-jsd mice, we first examined their ultrastructure in these mice, as well as in wild-type, SCARKO, and jsd mice. These complexes are characterized by a pair of parallel Sertoli cell membranes, with both adherens and tight junctions, which are sandwiched between layers of actin bundles and endoplasmic reticulum in wild-type mice (Supplemental Figure 3A). These complete structures were also observed in SCARKO and in jsd mice (Supplemental Figure 3B through E), although in jsd mice the tight junctions were not readily found. In SCARKO-jsd mice, although some basal junctional complexes consisting of ES and adherens junctions were observed (Supplemental Figure 3F), they appeared to be less common and/or less well formed. In addition, we could not find a tight junction in areas we sampled in these mice. Next we examined the distribution of vinculin, a protein associated with actin filaments at adherens junctions and ES (Vogl et al, 1993). In wild-type, SCARKO, and jsd testes, vinculin was observed in the cytoplasm of Sertoli cells and was brightest in the basal region of the tubule (Figure 5A through C). In SCARKO-jsd mice (Figure 5D), however, the cytoplasmic distribution of vinculin in the Sertoli cells was more uniform, and because there was no lumen formed in the tubules, the staining of vinculin occupied the whole tubule.
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Support of Spermatogonial Differentiation in SCARKO-jsd Mice
To determine whether failure of spermatogonial differentiation in
SCARKO-jsd mice was indeed a result of testosterone action on cells
other than Sertoli cells or whether Sertoli cell abnormalities were a
contributing factor, we treated SCARKO-jsd mice with a GnRH
antagonist (acyline) and an AR antagonist (flutamide), because it had
previously been shown that GnRH antagonist treatment alone or with flutamide
stimulated spermatogonial differentiation. The seminal vesicle and testis
weights were markedly reduced (Table
1), demonstrating that testosterone action was blocked in these
mice. As observed in jsd mice, treatment with GnRH antagonist plus
flutamide stimulated recovery of spermatogenesis up to the spermatocyte stage
in SCARKO-jsd mice (Table
2; Figure 6B).
Interestingly, restoration of differentiating germ cells by suppression of
testosterone greatly improved the organization of Sertoli cell nuclei in
testes of SCARKO-jsd mice (Figure
6D).
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Discussion |
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We considered that the abnormalities in Sertoli cells structure in the absence of androgen might also contribute to their inability to support spermatogonial differentiation in SCARKO-jsd mice. Most prominently, the positioning of Sertoli nuclei was drastically disrupted in testes of these mice, compared with previous reports of minimal disorganization and dislocation of Sertoli cell nuclei from the basement membrane in SCARKO mice (Tan et al, 2005; Wang et al, 2006). Because SCARKO-jsd mice can be a useful model for understanding the requirements for Sertoli cell organization, we further examined Sertoli cell structure in these mice.
The position of the cell nucleus is believed to be controlled by cytoskeletal elements, which in Sertoli cells appear to be the vimentin intermediate filaments, and their attachment to junctional complexes at the cell membrane (Vogl et al, 1993). Although others have shown that elimination of androgen action on Sertoli cells up-regulated vimentin mRNA levels (Wang et al, 2006) and increased degradation of vimentin protein (Show et al, 2003), our results showed normal localization of vimentin protein and morphologically intact intermediate filament connections between the nuclei and the hemidesmosome junctions in the Sertoli cells with nuclei near the basement membrane in SCARKO-jsd mice. This result suggests that neither disruption of the vimentin filament arrangement nor the loss of anchoring of Sertoli cell nuclei to the basal side of its plasma membrane appear to be the primary reason for the displacement of Sertoli cell nuclei. The only abnormality within the anchoring structure we noted was the increased thickness of basal laminae in the testes of both SCARKO and SCARKO-jsd mice, suggesting that the regular structure of the basement membrane does not fully develop when androgenic signaling is disrupted in Sertoli cells, as has also been noted in SCARKO mice (Wang et al, 2006).
Junctions between Sertoli cells and between Sertoli and germ cells can also contribute to maintenance of the Sertoli cell structure. Indeed, in SCARKO-jsd mouse testes electron microscopy showed that typical ES structures were rare and tight junctions could not readily be found. This is consistent with observations showing that eliminating expression of AR in Sertoli cells increases the permeability of the Sertoli cell barrier and decreases the levels of expression of components of the occluding junctions, claudin 3, claudin 11, and occludin (Meng et al, 2005; Wang et al, 2006).
Consistent with ultrastructural observations, vinculin, one of the component proteins of the ES (Vogl et al, 1993) did not show its generally basal localization observed in wild-type, SCARKO, and jsd mice and was more uniformly distributed throughout the seminiferous tubule of SCARKO-jsd mice. Because vinculin functions in adherens junctions between cells and in focal contacts with the basal lamina, absence of concentrated distribution of vinculin in testes of SCARKO-jsd mice may contribute to the sloughing of Sertoli cells from the basal area. The formation of tight junctions and the localized vinculin distribution were at least partly dependent on androgen action in the Sertoli cells, although altered vinculin distribution could, in part, be a consequence of the redistribution of the Sertoli cell cytoplasm. Similarly, the localization of the cadherincatenin complex, another component of adherens junctions, in the Sertoli cell ES, was also shown to be dependent on testosterone (Xia et al, 2005).
Although androgenic signaling in Sertoli cells is important to maintain their normal structure and nuclear positioning, presence of differentiated germ cells also appears to be involved. This conclusion is supported here by several lines of evidence. First, even with normal androgen action, jsd mice also showed mild disruption and sloughing of Sertoli cells. It should be noted that shrinkage of seminiferous tubules may also be a factor contributing to this abnormal organization. Second, dislocation of the nuclei and sloughing of Sertoli cells in SCARKO mice, which contain some differentiated germ cells, was much milder than that in SCARKO-jsd mice. In this case, the absence of androgen-dependent fluid secretion by Sertoli cells in SCARKO-jsd mice, which resulted in lack of lumen formation and loss of fluid pressure from the center of tubules, could also contribute to the disrupted organization of Sertoli cells and their nuclei. Third, the role of the differentiated germ cells in maintaining the positioning of the Sertoli cells and their nuclei was also strongly supported by the observation that restoration of germ cells by suppression of testosterone improved Sertoli cell organization in SCARKO-jsd mice.
We also are in the process of examining the overall changes in Sertoli cell gene expression in SCARKO-jsd by microarray comparison of these testes with jsd mice. Preliminary data suggest that the Sertoli cells in these SCARKO-jsd mice have equivalent expression of most markers of Sertoli cell maturation as jsd mice (Sharpe et al, 2003). Markers of mature Sertoli cells, SGP2 (Clu), GATA-1, and p27-Kip1 (Cdkn1b), were expressed at equivalent levels. Markers of immature Sertoli cells, AMH and aromatase (Cyp19a1), were not expressed. However there was a 4-fold higher expression of cytokeratin 1-18 (Krt18), a marker of immature Sertoli cells, in SCARKO-jsd mice than in jsd mice, indicating that Sertoli cell maturation may be somewhat abnormal.
Despite the disrupted organization and some structural and molecular defects, the absence of AR in the Sertoli cells of SCARKO-jsd mice cannot be the cause of the inability of spermatogonial differentiation to proceed. These testes are indeed capable of supporting spermatogonial differentiation when the testosterone levels and action were globally blocked. Thus, the target of testosterone producing the spermatogonial block in jsd mice must be some other AR-positive somatic cell within or outside the testis. In a related study, we have shown that increased temperature of testis alone is able to stimulate the spermatogonial differentiation in jsd mice even more effectively than does suppression of testosterone (Shetty and Weng, 2004). The association between testosterone levels, testicular temperature, and spermatogonial differentiation is currently under further investigation.
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Acknowledgments |
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Footnotes |
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W. Zhou, G. Wang, C. L. Small, Z. Liu, C. C. Weng, L. Yang, M. D. Griswold, and M. L. Meistrich Gene Expression Alterations by Conditional Knockout of Androgen Receptor in Adult Sertoli Cells of Utp14bjsd/jsd (jsd) Mice Biol Reprod, November 1, 2010; 83(5): 759 - 766. [Abstract] [Full Text] [PDF]
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 G. Wang, S. H. Shao, C. C. Y. Weng, C. Wei, and M. L. Meistrich Hormonal Suppression Restores Fertility in Irradiated Mice from both Endogenous and Donor-Derived Stem Spermatogonia Toxicol. Sci., September 1, 2010; 117(1): 225 - 237. [Abstract] [Full Text] [PDF]
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 G. Verhoeven, A. Willems, E. Denolet, J. V. Swinnen, and K. De Gendt Androgens and spermatogenesis: lessons from transgenic mouse models Phil Trans R Soc B, May 27, 2010; 365(1546): 1537 - 1556. [Abstract] [Full Text] [PDF]
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 M. Welsh, P. T. K. Saunders, N. Atanassova, R. M. Sharpe, and L. B. Smith Androgen action via testicular peritubular myoid cells is essential for male fertility FASEB J, December 1, 2009; 23(12): 4218 - 4230. [Abstract] [Full Text] [PDF]
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