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Analysis of the Testicular Phenotype of the Follicle-Stimulating Hormone ß-Subunit Knockout and the Activin Type II Receptor Knockout Mice by Stereological Analysis¹

Monash Institute of Reproduction (D.M.d.K.) and Department of Anatomy and Cell Biology (N.G.W.), Monash University, Melbourne, Australia; and Departments of Pathology (T.R.K., M.M.M.), Molecular and Cellular Biology (T.R.K., M.M.M.), and Molecular and Human Genetics (M.M.M.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Dr. D. M. de Kretser, Monash Institute of Reproduction and Development, Monash Medical Center, 246 Clayton Road, Clayton, Victoria 3168, Australia. E-mail: david.de.kretser{at}med.monash.edu.au

	Abstract

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This study evaluated the role of FSH and activin A on testicular function using quantitative stereological analysis of testicular cell types in mice with targeted disruption of genes encoding the FSH ß-subunit and the activin type IIA receptor (ActRIIA). Using the optical dissector technique, the numbers of Sertoli cells and germ cells per testis were determined. Testis weights in homozygous males lacking the FSHß gene or the ActRIIA gene were decreased approximately 60% compared with wild-type or respective heterozygotes. Sertoli cell numbers decreased in both homozygous mice by 30–39%, and there was a comparable decline in germ cell numbers in both models. The degree of germ cell attrition increased in the later stages of spermatogenesis from a 46% reduction of spermatogonia to a 60% decrease in round spermatids. As the FSH levels are decreased in both models, the cellular lesion in both is most likely due to the FSH deficiency. Although the decrease in the Sertoli cell complement represents one cause of lower germ cell numbers, the ability of Sertoli cells to nurture germ cells is compromised by the lower FSH levels, as shown by a decrease in the round spermatid to Sertoli cell ratios in both homozygous models. We conclude that the defects in FSH ß-subunit gene knockout and ActRIIA knockout mice are related to diminished FSH action on both Sertoli cell proliferation and the capacity of Sertoli cells to nurture germ cells.

	Introduction

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THE RELATIVE ROLES of FSH and testosterone (T) in the control of mammalian spermatogenesis have been the subject of some debate for years (1, 2, 3, 4, 5, 6, 7, 8, 9). In particular, the requirement for FSH has been questioned on several grounds. First, several studies have shown that T alone could maintain spermatogenesis after hypophysectomy (1, 2) or the withdrawal of gonadotropic support using antisera to GnRH (5, 6, 7) or GnRH antagonists (10). However, some of the conclusions of these studies have been questioned by the demonstration that high levels of T replacement cause a stimulation of FSH secretion by the pituitary in contrast to the suppression of this hormone observed when lower doses of T were used (9, 10).

Several recent studies have again challenged the requirement for FSH for the maintenance of spermatogenesis by removing the ability of the pituitary to produce FSH in certain murine models. Using hpg mice, which, due to the failure of GnRH secretion by the hypothalamus, have undetectable levels of FSH and LH, Singh et al. (11) showed that spermatogenesis could be initiated and maintained by the use of high doses of exogenous T. Although the mice treated in this manner were fertile, their testes were smaller than those of normal controls, and the numbers of testicular spermatids were decreased. However, other studies using passive immunization against FSH (5) in the rat have supported a role for FSH during spermatogenesis.

In the human, several studies have emphasized the importance of FSH in the stimulation of spermatogenesis in some men with hypogonadotropic hypogonadism as well in the restoration of spermatogenesis in normal men in whom spermatogenesis had been suppressed by testosterone treatment (12, 13, 14).

In a more specific approach to the removal of FSH, Kumar et al. (15) used targeted disruption of the gene encoding the ß-subunit of FSH in mice. They showed that male mice were fertile, and spermatogenesis proceeded successfully to completion. However, the testes from these mice were smaller in the absence of detectable FSH and normal concentrations of T. Using a similar approach, Matzuk et al. (16) disrupted the actions of the activins, a group of proteins with the capacity to stimulate FSH secretion, by a targeted disruption of the activin type IIA receptor (ActRIIA). These mice were fertile despite suppressed FSH levels, but although spermatogenesis proceeded to completion, testicular size was decreased.

It has been proposed that the smaller testicular size in both the FSH ß-subunit gene knockout and the ActRIIA gene knockout results from a decreased number of Sertoli cells in the testis. This postulate arises from the observation that FSH concentrations are suppressed in both models, and consequently, the FSH stimulation of Sertoli cell proliferation is lost (17). As it is well established that the total Sertoli cell number is a major determinant of the total sperm output of the testis (18, 19, 20), the spermatogenic capacity in both FSH-deficient models is impaired. However, to date no quantitative data are available to support these concepts or to determine whether, due to the absence of FSH, the ability of the Sertoli cells to support germ cells is compromised. The possibility exists that the small testes found in both of these models may result from different mechanisms, because messenger RNA and protein for both the activin ß_A- and ß_B-subunits are present in the testis (21, 22), and activin A can stimulate gonocyte numbers and inhibit Sertoli cell proliferation (23, 24) as well as stimulate spermatogonial division (25) and influence mitochondrial morphology in germ cells (26). This paper reports the results of quantitative cytological studies using stereological techniques that suggest that the decreased Sertoli cell number and a functional impairment of the capacity of Sertoli cells to support germ cells represent the major causes of the decreased testicular size.

	Materials and Methods

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Animals
Male mice containing a null mutation in the type IIA activin receptor gene, generated by Matzuk et al. (16), were used in the study. Additionally male mice containing a null mutation in the FSH and subunit gene, generated by Kumar et al. (15), were used. In both genetically modified mice, males were killed at 42 days, and then testis were fixed by immersion in Bouin’s fluid, transferred into 70% ethanol after 24 h, and prepared for stereological analysis as described below.

Preparation of testicular tissues and stereological techniques
One testis from each animal was cut into three parallel slices orthogonal to its long axis. After dehydration the slices were embedded in methacrylate resin (Technovit 7100, Kulzers GmbH, Wehrhem/Ts, Germany). One 20-µm section was cut from each block using an RM2055 microtome (Leica Corp., Nusstoch, Germany). The sections were stained with periodic acid-Schiff reaction and counterstained with hematoxylin.

Stereological analysis of these sections was performed using the optical dissector approach described by Wreford (27). Briefly, fields were sampled using a systematic uniform approach from a random start. Sampled fields were optically sectioned using a x100 (NA 1.4) oil immersion objective, and all nuclei coming into sharp focus within a known volume were counted to give a numerical density. The number of germ cells per testis was determined by multiplying this density by the processed volume of the testis. The criteria used to identify the cell types within the testis were described by Russell et al. (28).

Statistical analysis
Statistical analysis was performed using the SigmaStat 2.0 (Jandel Scientific, San Rafael, CA). Knockout, heterozygous, and wild-type animals were compared using a one-way ANOVA in conjunction with Tukey’s post-hoc test. In some cases the results determined for wild-type animals were pooled with the results for heterozygote animals to improve the power of the analyses. All data in tables and figures are presented as the mean ± SEM, and the level of significance at P < 0.05 is indicated.

	Results

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As previously, the male mice homozygous for both FSHß^-/- and the ActRIIA^-/- were fertile, and their mean testicular weight (Table 1) was significantly (P < 0.05) decreased by approximately 60% compared with that in wild-type mice and the respective heterozygotes (15, 16). Spermatogenesis appeared qualitatively normal in both knockouts and showed no obvious abnormalities compared with wild-type mice or the respective heterozygotes.

When we attempted to determine the specific stages at which germ cell attrition occurs by determining the ratios of more advanced germ cell types to earlier cell types, we found no significant difference due to the wide variance associated with ratios and the relatively small differences in conversion efficiency between sequential cell types. To simplify the comparison, spermatogonia and early (leptotene and zygotene) spermatocytes, all pachytene and diplotene spermatocytes, round spermatids (steps 1–8), and elongating spermatids (steps 9–16) were grouped together. Because there were no qualitative or quantitative differences between wild-type and heterozygote animals, they were pooled to form a single control group to further increase the power of the statistical analysis. Comparison of the conversion between these cell groupings is shown in Table 2. The ratio indicates a significantly (P < 0.05) increased attrition in the conversion of spermatogonia through to pachytene spermatocytes in the FSHß^-/- animal compared with that in the combined control group. An intermediate, but not significantly different, value was observed in the ActRIIA^-/- animals. Similarly, in the conversion of pachytene and diplotene spermatocytes to round spermatids there was significantly increased attrition in the FSHß^-/- animal compared with the combined control. As with the earlier conversion, the ActRIIA^-/- animal showed an intermediate, but not significantly different, value. The elongation process had similar efficiency in both knockouts, as evidenced by the ratio of elongating and elongated spermatids to round spermatids.

	Discussion

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This study confirms the earlier basic observation that FSHß^-/- and ActRIIA^-/- mice are fertile despite the presence of a significant decrease in testicular size. The results of the present study demonstrate that the reduction in testis weight is due to a very significant decrease in Sertoli and germ cell numbers. The data also suggest that the germ cell loss results from several mechanisms and that the stages of spermatogenesis that are affected may differ in the two models.

The 30–39% decrease in Sertoli cell number in the two models is consistent with the absence of FSH in the FSH ß-subunit knockout model and the lowered FSH levels in the ActRIIA knockout mice. It is probable that the absent or diminished FSH stimulation of Sertoli cell proliferation during fetal and postnatal life leads to the decreased Sertoli cell complement in these mice in keeping with the known action of FSH (17, 29). A number of manipulations leading to changes in the complement of Sertoli cells have clearly established the concept that the total sperm output of the testis is dependent on the number of Sertoli cells in the testis (18, 19, 20), and the results of this study support such a view. However, the results of this study also point to the need to consider the function of the Sertoli cells as well as their number. If the number of Sertoli cells were the only determinant, the ratio of germ cells to Sertoli cells should remain relatively constant across the controls, heterozygotes, and homozygotes. As shown in Table 3, the ability of Sertoli cells to support or nurture the maturation of round spermatids is compromised when these cells are exposed to low or absent FSH stimulation, as shown by the lower Sertoli cell to round spermatid ratios in both the FSHß^-/- and ActRIIA^-/- mice compared with that in wild-type controls. The ratios of 5.45 in the FSHß^-/- mice and 6.93 in the ActRcIIA^-/- mice are outside the range (8.34–11.2) found in wild-type and heterozygote mice.

The significantly lower ratios strongly suggest that the Sertoli cells in these mice are incapable of supporting the same numbers of germ cells as Sertoli cells maintained in a normal hormonal environment. The observation that the attrition of germ cells increases as the spermatogenic process progresses in both groups of knockout mice is also in keeping with the physiological support provided to germ cells by Sertoli cells.

The possibility that the changes in germ cell number may reflect the action of FSH or the activins on specific stages of spermatogenesis was explored in this study by examination of the progression of germ cell stages through this process. This approach involved the comparison of ratios of each germ cell type to more advanced stages in each knockout model and an examination of these ratios relative to each other. The data in Table 2 indicate that the ratios of spermatogonia and early stages of the first meiotic prophase (preleptotene, leptotene, and zygotene) to the later stages of meiotic prophase (pachytene and diplotene) are decreased only in the FSHß^-/- mice. Similarly, the completion of meiosis is significantly impaired in the FSHß^-/- mice, as shown by the lower ratios of pachytene/diplotene spermatocytes to round spermatids. This is in keeping with earlier observations that FSH is required throughout the spermatogenic process, except for the completion of spermiogenesis beyond the round spermatid stage (5, 6, 7, 8). It is surprising that as FSH levels are low in ActRIIA^-/- mice, no differences were noted in these ratios in these mice. This result may reflect the difference in the degree of FSH suppression, as FSH is absent in FSHß^-/- mice compared with the 66% suppression of FSH noted in ActRIIA^-/- mice reported previously (16). As Sertoli cell numbers were comparably decreased in the two models, the data suggest that the effect on Sertoli cell proliferation is more sensitive to lowered FSH levels.

In view of the observations that activin A can stimulate spermatogonial proliferation (23, 25) and gonocyte numbers (24), and activin and its receptors are present in germ and Sertoli cells (30, 31), we examined the progression of A and I spermatogonia to type B spermatogonia and preleptotene stages. These ratios in the wild-type (2.97), heterozygotes (FSHß^+/-, 2.99; ActRIIA^+/-, 2.95), and FSHß^-/- (2.95) were all similar, but the ratio in the ActRIIA^-/- mice (2.49), although lower, was not statistically significantly different. The use of larger numbers of mice may clarify the importance of this observation. Alternatively, treatment of both ActRIIA^-/- and FSHß^-/- mice with recombinant FSH may magnify the differences.

The observation that the FSHß^-/- mice are fertile has prompted the argument that FSH in not necessary for the completion of spermatogenesis and fertility. However, the germ cell conversion ratios in the FSHß^-/- mice are consistently below normal at many of the steps in spermatogenesis. These data again emphasize that although these mice are fertile, spermatogenesis is impaired in the absence of FSH over and above the reduction in Sertoli cell number. Such conclusions are in keeping with considerable data in several species that clearly demonstrate actions of FSH on spermatogenesis (5, 12, 32, 33). However, the normal ratio for the conversion of type A and I spermatogonia to type B in FSHß^-/- mice is surprising in view of several studies in primates and humans that suggest that the withdrawal of FSH can cause a marked decrease in type B spermatogonia (34, 35).

The observations provide some insights onto the control of sperm output in humans. Some men have been noted to have smaller than normal testes and sperm counts that are below normal yet remain fertile. The data presented here suggest that this phenomenon could represent a disturbance of Sertoli cell proliferation based on subnormal FSH stimulation. Although such men may have normal or elevated levels of FSH, the possibility of inactivating FSH receptor mutations may be one mechanism underlying such phenotypic features, as several men have been described with this disorder (33). They had severe reduction in sperm concentration associated with small testes, yet were fertile.

The observation that the testicular phenotype in FSHß^-/- mice could be rescued by the introduction of a human FSHß transgene that is selectively expressed in the pituitary gland (36) clearly indicates that these changes are FSH dependent. Our unpublished studies also indicate that the lesion in FSHß^-/- mice does not progress with age, as mice between 6–12 months remain fertile without any significant decline in the number of offspring produced.

It is not surprising that this study has shown that the spermatogenic defect in the FSHß^-/- mice is more complex that the simplistic view that it results solely from a decrease in Sertoli cell number because it is generally agreed that as there are no FSH receptors on germ cells, any action of FSH must be transmitted by an altered Sertoli cell physiology. To date the nature of these changes have largely remained elusive, but the existence of models such as these provide experimental models to elucidate these changes. Finally, this study demonstrates the value of detailed quantitative studies of the germ cell and Sertoli cell populations in mice in which targeted disruption of a gene results in a decline in testis weight despite the maintenance of normal fertility. Failure to undertake these studies may result in failure to obtain information of value in unraveling the importance of hormones and growth factors in the multifactorial control of spermatogenesis.

	Acknowledgments

 
The authors thank Qing Song for her expert skills in quantitation of the cell types within the testis.

	Footnotes

 
¹ This work was supported by a grant from the Australian Research Council (09600657).

Received November 30, 2000.

	References

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