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RESEARCH |
Department of Veterinary Anatomy and 1 Department of Global Agricultural Sciences, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan, 2 Department of Anatomy, Kyorin University School of Medicine, Mitaka, Tokyo, 181-8611, Japan, 3 Department of Cell Pharmacology, Nagoya University, Graduate School of Medicine, 65 Tsurumai, Showa, Nagoya 466-8550, Japan, 4 The Child Health Research Institute, 72 King William Rd, North Adelaide, South Australia 5006, Australia
Correspondence should be addressed to Y Kanai; Email: aykanai{at}mail.ecc.u-tokyo.ac.jp
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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On the other hand, Af-6 (also known as Afadin) is an integral component of tight and adherens junctions (Yamamoto et al. 1997, Mandai et al. 1997), which is essential for epithelial cell–cell contact and cell polarity (Ikeda et al. 1999, Zhadanov et al. 1999). In polarized epithelial cells, Af-6 is localized at the actin-based cell–cell adhesion sites such as tight and adherens junctions (Mandai et al. 1997, Yamamoto et al. 1997), where it associates with a tight junction protein ZO-1 (Yamamoto et al. 1997), immunoglobulin-like cell adhesion molecules, nectin (Miyahara et al. 2000, Takai & Nakanishi 2003) and junctional adhesion molecule (Ebnet et al. 2000). Af-6 has also been shown to bind to a number of signaling molecules such as Ras family GTPases including Rap1 and Ras (Kuriyama et al. 1996, Linnemann et al. 1999, Boettner et al. 2000) and subsets of Eph-related receptor protein tyrosine kinases (Hock et al. 1998, Buchert et al. 1999). Moreover, several biochemical analyses suggest that Af-6 may also possess a signal-mediating function, regulating the dynamic junction regeneration and cell adhesion in response to specific extracellular signals (Su et al. 2003, Radziwill et al. 2003).
During mammalian gametogenesis, the dynamic formation and degeneration of the junctional alignment in both Sertoli and granulosa cells are important in spermiation and spermatogenic cell movement across the seminiferous epithelium (spermatogenesis) (Cheng & Mruk 2002) and in ovulation and follicle development (oogenesis) (Fair 2003). Most interestingly, Af-6 has been shown to be one substrate of Usp9x in MDCK cells (Taya et al. 1998), although no appreciable genetic interaction was found between Usp9x ( faf) and Af-6 (canoe) homologues in Drosophila eye development (Chen et al. 2000). In MDCK cells, Af-6 interacts with Usp9x both in vivo and in vitro, Af-6 is ubiquitylated in intact cells and Usp9x prevents the ubiquitylation of Af-6 in this cell line. In mouse two-cell embryos, the depletion of Usp9x protein also induces the rapid decline of total Af-6 expression level and its mislocalization at the apical surface of blastomeres, which results in an inhibition of cell adhesive events (Pantaleon et al. 2001). Therefore, with regard to a stage-specific Usp9x expression pattern in Sertoli and granulosa cells (Noma et al. 2002, this study), these findings suggest the possibility that the post-translational regulation of Af-6 by Usp9x may be one potential regulatory system of cell adhesion dynamics in both spermatogenesis and oogenesis. However, at present there is little information on the stage-specific changes in Af-6 localization and its association with Usp9x expression in gametogenesis, except for the report showing an enrichment of Af-6 in Sertoli–Sertoli and Sertoli–spermatid junctions of adult testis (Ozaki-Kuroda et al. 2002).
To clarify a possible association between Af-6 and Usp9x in mammalian gametogenesis, in this study we examined the expression patterns of Af-6 and Usp9x in the testis and ovary by immunohistochemistry. Moreover, we analyzed the changes in their expression patterns in mice treated with or without pregnant mare serum gonadotropin (PMSG), a follicle-stimulating hormone (FSH)-like hormone, which was shown by in vitro experiments to affect the cell adhesiveness of Sertoli cells in the testis (Janecki et al. 1991) and granulosa cells in the ovary (Ben-Ze’ev 1987, Ben-Ze’ev & Amsterdam 1987). As a result, the present study is the first to demonstrate a close correlation between Af-6 and Usp9x expression patterns in both Sertoli and granulosa cells during mouse gametogenesis.
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Materials and Methods |
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Immunohistochemistry
The testes and ovaries were isolated at various stages (five mice each at postnatal stage and four adult 8-week mice of each sex), and fixed in Bouin’s solution for 4 h. They were dehydrated in ethanol, cleared in xylene, and then routinely embedded in paraffin. Paraffin sections were cut (5 µm in thickness) from at least four independent gonadal samples at each stage, and applied to immunohistochemistry using anti-Af-6 or Usp9x Ab as described previously (Kanai-Azuma et al. 2000, Noma et al. 2002). In brief, deparaffinized sections were first incubated with anti-Af-6 or anti-Usp9x Ab (each 2.5 µg/ml) at 4 °C for 12 h. After washing with Tris–buffered saline (pH 7.5) several times, the reaction was visualized by horseradish peroxidase (HRP)-labeled goat anti-rabbit secondary Ab in combination with a Tyramide Signal Amplification kit (NEN Life Sciences Product, Wellesley, UK). For the comparative immunohistochemical analysis of the control and PMSG-treated gonads (three males at 8 weeks and three females at 3 weeks in each group), the procedures for fixation, embedding and immunohistochemical staining were performed as carefully as possible under the same conditions in order to evaluate the relative immunoreactivity. The same staining condition in each sample was also confirmed by the similar intensities of anti-Af-6 staining in Leydig or theca cells between control and PMSG-treated samples (asterisks in Fig. 5a, b, e and f
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Immunoblot
The testes (8 weeks; three males) and ovaries (3 weeks; four females) were isolated from the mice at 48 h post-PMSG treatment as described above. Each tissue was washed twice with ice-cold PBS, homogenized in RIPA buffer (50 mM Tris–HCl, (pH 7.5), 150 mM NaCl, 0.5 mM EDTA, 1% Triton X, and 1 xprotease inhibitor cocktail (Roche Diagnostics, Basel, Switzerland)), and centrifuged at 10 000 g at 4 °C for 30 min. After the protein concentration of each supernatant was determined by the BCA Protein Assay Reagent Kit (Pierce Biotechnology, Rock-ford, IL, USA), 10 µg of each sample was boiled with non-reduced SDS sample buffer, and electrophoresed in a 4–20% gradient gel. After the gels were transfered to nylon membranes, the blots were incubated with anti-Usp9x or anti-Af6 Ab (50 ng/ml each). The labeled protein was then visualized with HRP-labeled goat anti-rabbit IgG Ab in combination with the enhanced chemiluminescence detection kit (Amersham Pharmacia Biotech, Piscataway, NJ, USA) as described previously (Kanai et al. 1996). In addition, approximately equal amounts of protein sample per lane were confirmed by Coomassie brilliant blue (CBB) staining of both the replica gels and the lower part of the identical gels (the gel pieces corresponding to the migration area with less than 30 kDa, which were separated before membrane transfer).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionAcknowledgementsReferences |
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). To examine the localization of Af-6, a substrate of Usp9x, we first examined the expression of Af-6 in the developing testes by conventional immunohistochemistry using paraffin sections. As a result, Af-6 reactions were detected predominantly in Sertoli cells, Leydig cells and some interstitial stromal cells, but not in any germ cells, throughout the postnatal and adult stages (Fig. 1a–d). During postnatal periods, Af-6 reactions were strongly observed in Sertoli cells from newborn to 4 weeks (Fig. 1a–c), although they were significantly reduced in Sertoli cells of 8-week testes (Fig. 1d). Moreover, the distribution pattern of both Af-6 and Usp9x reactions was found in a stage-dependent manner, diffuse in the Sertoli cell cytoplasm at stages VII–X (lower right panels in Fig. 1d and e), versus restricted to the basal area of the cytoplasm at stages XI–VI (lower left panels in Fig. 1d and e). These findings therefore suggest that Af-6 is co-localized with Usp9x in Sertoli cells, and both Af-6 and Usp9x show some stage-dependent synchronous changes in their intracellular distribution.
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). Confocal analysis also revealed a stage-dependent alteration in their intracellular localization at the sites of the actin-mediated junctions of Sertoli cells. In short, at stages VII–X Af-6 reactions were diffusely detected in the basal compartment around spermatogonia and in the area adjacent to spermatocytes and spermatids, which include the Sertoli–Sertoli and Sertoli–spermatid ectoplasmic specializations (yellow; small and large arrows in Fig. 2a respectively). Moreover, positive reactions with anti-Usp9x Ab were more widely observed throughout the whole cytoplasm of Sertoli cells at these stages (Fig. 2c). In contrast to such a diffuse distribution pattern of both Af-6 and Usp9x at stages VII–X, their reactions were more restricted to these two junctional sites of the ectoplasmic specialization in Sertoli cells at stages XI–VI (yellow; small and large arrows in Fig. 2b and d). These findings clearly suggest that Af-6 is co-localized with Usp9x at the sites of the inter-Sertoli junctional complex and Sertoli–spermatid adherens junction, especially at stages XI–VI, and that both Af-6 and Usp9x molecules may synchronously transit between the junctional sites and the cytoplasm in a stage-dependent manner.
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). The present immunohistochemical analysis clearly showed that Af-6 expression resembles the Usp9x expression pattern during follicle development (Fig. 3a–d). In the 1-week ovary, Af-6 expression was predominantly found in granulosa cells of primordial follicles (arrows in Fig. 3a). In granulosa cells of ovaries from 2-week to 8-week adults, such reactions were continuously observed in all primordial and primary follicles and weakly in some secondary follicles, but they completely disappeared in the late-secondary and Graafian follicles of 4-week and 8-week ovaries (Fig. 3c and d). In addition to the expression of Af-6 in granulosa cells, Af-6 was strongly expressed in theca cells and some stromal cells of the ovarian interstitium (asterisks in Fig. 3b–d), but not in oocytes at any stages, which showed similarities to its expression in Leydig cells and some stromal cells of the testicular interstitium as described above (asterisks in Fig. 1a–d
). Such strong Af-6 expression in interstitial steroidogenic cells in both testes and ovaries suggests its possible involvement in gonadal steroidogenesis, but the exact role of Af-6 in these cells is unclear. By using confocal laser scanning microscopy, we also investigated the intracellular localization of Af-6 and Usp9x in granulosa cells of the adult ovary (Fig. 4a and b). Positive reactions of both Af-6 and Usp9x were observed diffusely throughout their cytoplasm in granulosa cells of the primordial and primary follicles. We could not detect any Af-6 reaction at specialized cell–cell junctions, such as adherens junctions, in granulosa cells.
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) and strongly in granulosa cells (Fig. 5e and f) as judged by its expression levels in Leydig cells and theca cells (asterisks in Fig. 5a, b, e and f) respectively. In Sertoli cells, PMSG treatment resulted in a weak enhancement of Af-6 expression levels in the whole cytoplasm of cells at stages VII–X (lowermost plates in Fig. 5a and b) and in their basal compartment at stages XI–VI (middle plates in Fig. 5a and b), although no appreciable alterations in its intracellular distribution pattern was detected. This clearly suggested that PMSG treatment slightly enhances the Af-6 expression level, but does not alter its intracellular distribution in Sertoli cells. Similar to Af-6 up-regulation in PMSG-treated testes, Usp9x expression also appeared to be slightly enhanced in the whole cytoplasm at stages VII–X (lowermost plates in Fig. 5c and d) and in their basal compartment at stages XI–VI (middle plates in Fig. 5c and d). Only a weak Af-6 enhancement in Sertoli cells of the PMSG-treated testes may possibly be due to masking the effects of exogenously administrated PMSG by a constant high level of the endogenous circulatory FSH in normal adult male mice. In PMSG-treated ovaries, the expression levels of both Af-6 and Usp9x showed no appreciable change in granulosa cells of primordial and primary follicles (middle plates in Fig. 5e–h). However, the reactivity of both Af-6 and Usp9x was strongly up-regulated in granulosa cells of the late-secondary and Graafian follicles (lowermost panels in Fig. 5f and h), in contrast to no detectable reaction in the control ovary at the same stages (lowermost panels in Fig. 5e and g). These observations indicated that PMSG treatment synchronously enhances the expression levels of Af-6 and Usp9x in both Sertoli and granulosa cells (Table 1). In addition, the number of late-secondary and Graafian follicles was found to have increased in PMSG-treated ovaries compared with that of the control ovary, but no appreciable histological changes were detected in the PMSG-treated testes.
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). Immunoblot experiments using the testicular and ovarian extracts clearly demonstrated that anti-Af-6 and anti-Usp9x Ab specifically recognized a specific single band of approximately 205 and 220 kDa respectively. These data clearly confirmed the high specificity of each Ab as was demonstrated in previous studies (Taya et al. 1998, Kanai-Azuma et al. 2000). PMSG treatment revealed an enhancement of Usp9x expression level, slightly in the testes and strongly in the ovaries (right-hand plates in Fig. 6a and b), which is consistent with the immunohistochemical data shown in Fig. 5c, d, g and h. Moreover, Af-6 expression was moderately up-regulated by PMSG treatment in the ovary (left-hand plates in Fig. 6b), but no appreciable difference between control and PMSG-treated testes was detected in the present immunoblot experiments (left-hand plates in Fig. 6a). Since Af-6 is highly expressed in the testicular interstitial cells (asterisks in the top panels of Fig. 5a and b), this result may be due to their masking a weak Af-6 up-regulation in Sertoli cells of the PMSG-treated testes.
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Discussion |
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In the testis, the seminiferous epithelium contains two unique types of actin-mediated intercellular junction: Sertoli–Sertoli junctional complex (blood–testis barrier) and Sertoli–spermatid junctions (Russell & Grisword 1993). During spermatogenesis, preleptotene spermatocytes migrate progressively from the basal to the adluminal compartments of the seminiferous epithelium traversing the Sertoli–Sertoli junction at stages VIII–IX (Cheng & Mruk 2002, Lui et al. 2003). At the same stages, matured spermatozoa are released from the apical area of Sertoli cells into the lumen (i.e. spermiation). These two events are accompanied by extensive restructuring of both Sertoli–Sertoli and Sertoli–spermatid junctions. The present immunohistochemical study suggests that Usp9x, a deubiquitylating enzyme, and Af-6, a cell junction protein and a substrate of Usp9x, are co-localized at the sites of the actin-based junctions in a stage-dependent manner. In brief, both Af-6 and Usp9x showed a diffuse distribution pattern in Sertoli cell cytoplasm at stages VII–X, while their reactions were more enriched in these two sites of Sertoli–Sertoli junctional complex and Sertoli–spermatid junction at stages XI–VI. This observation clearly suggests that Usp9x may possibly stabilize Af-6 at these actin-mediated junctions more efficiently at stages XI–VI than those at stages VII-X, which may result in the loosening of these junctions at stages VII-X. This is consistent with the fact that junctional degradation and reconstruction by spermiation and germ cell movement occurs at stages VIII–IX.
Af-6 (Afadin) is also shown to play an important role in nectin (an immunoglobulin-like adhesion molecule)-based intercellular adhesion by directly connecting nectin to the actin cytoskeleton (Takai & Nakanishi 2003). In the seminiferous epithelium, Nectin-2, as well as Af-6, is also restricted to the Sertoli–Sertoli and Sertoli–spermatid junctions in Sertoli cells (Ozaki-Kuroda et al. 2002, Mueller et al. 2003). Nectin-2-deficient mice exhibit male-specific infertility and have defects in the later steps of sperm morphogenesis in the testis (Bouchard et al. 2000, Ozaki-Kuroda et al. 2002). Interestingly, in these mutant testes, the spermatids at steps 1–10 of spermiogenesis were normal, but at later steps (after step 11), the defects involving irregular shapes and prominent translucent vesicles were observed in all nuclei. The period when such spermatid defects appeared was clearly coincident with stages XI–VI (i.e. spermatids at steps 11–15) when both Usp9x and Af-6 were restricted to the Sertoli–spermatid junction in this study. Therefore, such a close correlation between the abnormal spermatid differentiation in Nectin-2-null testis and Usp9x localization at its junctional site suggests that Usp9x may contribute to the proper morphogenesis of spermatids by stabilizing the nectin-2–Af-6 complex in the Sertoli–spermatid junction in mouse spermiogenesis.
In contrast to the restricted localization of Af-6 and Usp9x at these two unique actin-based junctions in Sertoli cells, both Af-6 and Usp9x in the ovary showed a diffuse localization pattern in the whole cytoplasm of granulosa cells in this study. However, their expression in granulosa cells exhibited a stage-dependent pattern during follicular development: a high expression in primordial and primary follicles, but a rapid decline in the late-secondary to Graafian follicle. E-cadherin was previously shown to be involved in junctional dynamics of granulosa cells (Machell et al. 2000, Sundfeldt et al. 2000, Peluso et al. 2001). Interestingly, E-cadherin expression also shows a similar decline in granulosa cells of the late-secondary and Graafian follicles (Machell et al. 2000). These findings may therefore reflect the decrease in adherens junctions of maturing follicles, especially at the preovulatory stage (Rotmensch et al. 1986, Amsterdam & Rotmensch 1987). Such a weak cell–cell adhesiveness among granulosa cells may likely be required for the rapid increase of the follicular volume and the subsequent ovulation during follicular maturation.
At present, there is a poor understanding of molecular mechanism of the adherens junction dynamics, and no evidence of the involvement of tight junction in granulosa cells of mammalian ovary. However, Schuster et al.(2004) have recently shown that, in the avian ovarian follicle, occludin, a tight junction protein, is expressed in granulosa cells of the immature follicle, and its expression levels clearly decrease with follicular maturation. They also demonstrated that FSH is capable of up-regulating occludin expression level in avian granulosa cells through a synergistic manner with activin A in vitro (Schuster et al. 2004). This is consistent with the present immunohisto-chemical data showing a strong enhancement of Af-6 expression in granulosa cells of late-secondary and Graafian follicles by PMSG treatment in vivo. It is well known that FSH plays a key role in the control and maintenance of normal gametogenesis through Sertoli cells (Nieschlag et al. 1999, Heckert & Griswold 2002) or ovarian granulosa cells (Gromoll et al. 1996, O’Shaughnessy et al. 1996). Most interestingly, in this study, to accompany an increase of Af-6 expression, Usp9x was also found to be synchronously up-regulated in granulosa cells of the late-secondary and Graafian follicles in the ovaries treated with PMSG. These findings clearly emphasize a close association with Af-6 and Usp9x expression in granulosa cells, and further support the theory that Af-6 protein is regulated by Usp9x in these cells. This is also consistent with the present data showing a weak, but synchronous, enhancement of both Af-6 and Usp9x in Sertoli cells with PMSG treatment, although FSH function is not essential for Sertoli cell junction dynamics in the mouse testis (Kumar et al. 1997, Dierich et al. 1998, Abel et al. 2000). Only a weak Af-6 enhancement in Sertoli cells of the PMSG-treated testes may possibly be due to the masking of the effects of exogenously administered PMSG by a constant high level of the endogenous circulatory FSH in normal adult male mice. Additional experiments using FSH-depleted mouse models are required in future studies. Moreover, whether PMSG treatment promotes the Af-6 protein stability via Usp9x function or whether its signaling directly up-regulates Usp9x expression at the transcriptional level require further analysis.
Interestingly, as well as Af-6, ß-catenin, an intracellular component of the cadherin-mediated cell adhesion complex, is shown to be a substrate of Usp9x (Taya et al. 1999). This clearly suggests the possibility that Usp9x regulates the stability of ß-catenin, as well as Af-6, in Sertoli or granulosa cells during gametogenesis. In the testis, the cadherin/ß-catenin complex has been shown to be one of the functional units regulating the actin-based adherens junction dynamics in Sertoli cells (Lee & Yan Cheng 2003). Moreover, ß-catenin is reported to be localized in the Sertoli–Sertoli junctional complex and Sertoli–spermatid junction of Sertoli cells (Byers et al. 1994), which suggests the co-localization of ß-catenin and Usp9x at these two sites in Sertoli cells. However, in the testis, ß-catenin expression shows no noticeable stage-dependent change throughout the cycle of seminiferous epithelium (Byers et al. 1994, Johnson & Boekelheide 2002). This is in contrast to the stage-specific changes in the intracellular localization of both Usp9x and Af-6 at these junctional sites in this study. In the ovary, E-cadherin was shown to be expressed in granulosa cells in a stage-dependent manner (Machell et al. 2000), which shows a similar pattern to the present data of a strong expression of both Usp9x and Af-6 in primordial and primary follicles, but their rapid decline with follicular maturation. Moreover, ß-catenin is highly expressed in granulosa cells (Sundfeldt et al. 2000). However, in the ovary, in contrast to the rapid decline of both Usp9x and Af-6 from the late-secondary follicle stage (Noma et al. 2002, this study), ß-catenin was continuously expressed in granulosa cells of the late-secondary and Graafian follicles (Sundfeldt et al. 2000). These findings therefore suggest that the ß-catenin expression level may not be regulated mainly by an Usp9x-mediated pathway in both Sertoli and granulosa cells. This is also consistent with a previous study (Pantaleon et al. 2001) showing a correct localization of ß-catenin, but a rapid loss of Af-6, at cell–cell contacts in Usp9x-depleted embryos.
In conclusion, the present immunohistochemical study is the first to demonstrate a close correlation between Af-6 and Usp9x expression patterns in both Sertoli and granulosa cells in a stage-specific manner during mouse gametogenesis. This clearly illustrates that Usp9x may deubiquitylate Af-6, promoting its protein stability in Sertoli and granulosa cells of mouse gonads, especially at the sites of the actin-based junctions of Sertoli cells in the testis. With regard to the recent report showing that neuronal overexpression of the Usp9x homologue ( faf) enhances neuromuscular junction formation during Drosophila synaptic development (DiAntonio et al. 2001), the present findings therefore support the hypothesis that Af-6 and Usp9x interaction may be one potential pathway to regulate the cell adhesion dynamics of both Sertoli and granulosa cells in mammalian gametogenesis.
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Acknowledgements |
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Footnotes |
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References |
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