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Genes to Cells (2006) 11, 1125-1132. doi:10.1111/j.1365-2443.2006.01006.x
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Role of cell adhesion molecule nectin-3 in spermatid development

Maiko Inagaki1, Kenji Irie1, Hiroyoshi Ishizaki2,3, Miki Tanaka-Okamoto2, Jun Miyoshi2 and Yoshimi Takai1,*

1 Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Japan
2 Department of Molecular Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan
3 KAN Research Institute Inc., 93 Chudoji-Awatamachi, Shimogyo-ku, Kyoto 600-8815, Japan


   Abstract
Top
 Abstract
Introduction
 Results
 Discussion
 Experimental procedures
 References
 
Seminiferous epithelia of the testes contain two types of intercellular junctions: Sertoli–Sertoli junctions and Sertoli–spermatid junctions. The former junctions are equipped with tight and adherens junctions while the latter junctions are not. Ca2+-independent immunoglobulin-like cell-cell adhesion molecules, nectin-2 and nectin-3, asymmetrically localize at the Sertoli cell side and at the spermatid side of Sertoli–spermatid junctions, respectively. They heterophilically trans-interact to make contact between the two cells. Nectin-2–/– mice have shown male-specific infertility, disrupted Sertoli–spermatid junctions and morphologically impaired spermatid development. Here we report testicular phenotypes of nectin-3–/– mice exhibiting male-specific infertility. Nectin-3–/– mice had defects in the later steps of sperm morphogenesis including distorted nuclei and abnormal distribution of mitochondria, as well as in localization of nectin-2 at the Sertoli–spermatid junctions. Transplantation of wild-type spermatogenic stem cells into the nectin-3–/– testes partially rescued these defects in sperm morphogenesis. These results indicate that the heterophilic trans-interaction between nectin-2 and nectin-3 is essential for the formation and maintenance of Sertoli–spermatid junctions that plays a critical role in spermatid development.


   Introduction
Top
 Abstract
 Introduction
Results
 Discussion
 Experimental procedures
 References
 
Sertoli cells form rigid junctional complexes with neighboring Sertoli cells (Sertoli–Sertoli junctions) and constitute the single-layered epithelium (Cheng & Mruk 2002). On the other hand, spermatogenic cells are developmentally embraced and cultivated by Sertoli cells during spermatogenesis. Spermatogonia proliferate to give rise to spermatocytes, going through meiosis. The resultant haploid spermatids undergo their characteristic morphological development (spermiogenesis). During the latter half of spermiogenesis, spermatids form prominent cell-cell junctions with Sertoli cells called Sertoli–spermatid junctions that are loosened when spermatids are released as spermatozoa.

Sertoli–Sertoli junctions are equipped with tight junctions (TJs) as well as adherens junctions (AJs), which serve as the "blood–testis" barrier. TJs function as a barrier that prevents solutes and water from passing between neighboring cells and as a fence between the apical and basolateral plasma membrane domains (Tsukita et al. 2001; Tsukita & Furuse 2002). Claudins are key Ca2+-independent cell-cell adhesion molecules (CAMs) which constitute a family of over 27 members (Tsukita et al. 2001; Tsukita & Furuse 2002). Occludin is another CAM at TJs, although its function has not fully been understood. Claudins and occludin are associated with the actin cytoskeleton through peripheral membrane proteins, such as ZO-1, ZO-2, and ZO-3. Junctional adhesion molecules (JAMs) that belong to the Ca2+-independent immunoglobulin (Ig)-like CAM also localize at TJs and interact with ZO proteins (Tsukita et al. 2001; Tsukita & Furuse 2002). JAMs comprise a family consisting of four members. AJs are defined as closely apposed plasma membrane domains reinforced by a dense cytoplasmic plaque where actin filament (F-actin) bundles are undercoated (Farquhar & Palade 1963). In epithelial cells, E-cadherin and nectins are major CAMs at AJs (Perez-Moreno et al. 2003; Takai et al. 2003; Takai & Nakanishi 2003). E-Cadherin, a member of the cadherin family expressed in epithelial cells, is associated with the actin cytoskeleton through peripheral membrane proteins, including {alpha}- and ß-catenins, vinculin, and {alpha}-actinin (Gumbiner 2000; Nagafuchi 2001; Perez-Moreno et al. 2003). Nectins, which constitute a family of four members, nectin-1, nectin-2, nectin-3 and nectin-4, have recently emerged as Ca2+-independent Ig-like CAMs at AJs (Shimizu & Takai 2003; Takai et al. 2003; Takai & Nakanishi 2003; Sakisaka & Takai 2004). All nectins are associated with the actin cytoskeleton through afadin, an F-actin- and nectin-binding protein. Claudin-11, occludin, N-cadherin, and nectin-2, but not nectin-1 or nectin-3, have been shown to localize at Sertoli–Sertoli junctions (Cheng & Mruk 2002; Ozaki-Kuroda et al. 2002).

In contrast to Sertoli–Sertoli junctions, the molecular mechanisms of forming Sertoli–spermatid junctions are unclear. Unlike at typical AJs, the existence of the cadherin-catenin system at Sertoli–spermatid junctions has been questioned, but recent studies have suggested that the cadherin-catenin system does localize at Sertoli–spermatid junctions (Cheng & Mruk 2002). However, it remains unknown whether the cadherin-catenin system is essential for the formation of Sertoli–spermatid junctions. We have previously shown that nectin-2, nectin-3 and afadin co-localize with the F-actin that underlies Sertoli–spermatid junctions (Ozaki-Kuroda et al. 2002). Nectin-2 and nectin-3 reside specifically in Sertoli cells and spermatids, respectively, suggesting the formation of a hetero-trans-dimer between nectin-3 in spermatids and nectin-2 in Sertoli cells. The nectin-based adhesive membrane microdomains show one-to-one linkage with each F-actin bundle at Sertoli–spermatid junctions. Nectin-2–/– mice show the male-specific infertility phenotype and have defects in the later steps of sperm morphogenesis, exhibiting distorted nuclei and abnormal distribution of mitochondria (Bouchard et al. 2000; Ozaki-Kuroda et al. 2002). In these mice, the structure of Sertoli–spermatid junctions is severely impaired, and the localization of nectin-3 and afadin is disorganized, whereas Sertoli–Sertoli junctions appear to be organized normally (Ozaki-Kuroda et al. 2002). In addition, spermatozoa of the nectin-2–/– mice have a defect in binding to the zona pellucida and oocyte penetration (Mueller et al. 2003). Thus, it has been established that nectin-2 is essential for the formation and maintenance of Sertoli–spermatid junctions. However, this role of nectin-3 remains unexplored. We have generated nectin-3–/– mice that show male-specific infertility (Inagaki et al. 2005) and characterized here their testicular phenotypes.


   Results
Top
 Abstract
 Introduction
 Results
Discussion
 Experimental procedures
 References
 
Male-specific infertility of the nectin-3–/– mice

To examine the role of nectin-3 in male fertility, male nectin-3–/– mice at the age of 14–20 weeks were each housed with female wild-type mice at the age of 10–18 weeks that were proven to be fertile. Male nectin-3–/– mice showed normal mating behavior and each mouse produced copulation plugs on numerous occasions. However, no offspring were ever produced from these matings (Table 1). These results indicate that male nectin-3–/– mice are infertile. On the other hand, female nectin-3–/– mice were fertile (data not shown).


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  		Table 1 Male specific infertility of nectin-3–/– mice
 
Severely malformed spermatozoa in the nectin-3–/– testes

Histological analyses of testes from the adult nectin-3–/– mice did not show obvious abnormalities in Sertoli cells (Fig. 1A, Nectin-3–/–), spermatogonia, and spermatocytes. The 16 "steps" of mouse spermiogenesis have been defined for the morphological change of spermatids (Russell et al. 1990). At steps 12–16 of spermiogenesis, where elongated spermatids are formed, abnormalities of spermatids involving irregular shapes were detected in all the nuclei examined (Fig. 1A, Nectin-3–/– inset; data not shown). Phase contrast microscopy revealed that the spermatozoa of the male nectin-3–/– mice showed severe malformation of the head and the midpiece (Fig. 1B). Despite their severe defects, however, nectin-3–/– spermatozoa were viable and some motile sperms were observed when squeezed out from the cauda epididymis (data not shown) although the motility of the nectin-3–/– sperm was too weak to be measured by Computer Assisted Sperm Analyzer (data not shown, Nakanishi et al. 2004). The disorganized mitochondrial sheath appeared to indicate impairment of the spermatozoan energy metabolism. Thus, male nectin-3–/– mice were sterile due to functionally impaired spermatogenesis.


Figure 1
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  		Figure 1  Severely malformed spermatozoa in the nectin-3–/– testes. (A) Histological analysis of the testes from adult nectin-3–/– mice. Insets indicate step 12–13 spermatids at stage XII-I. The stages of the cycle of the seminiferous epithelium were identified by applying classical criteria (Russell et al. 1990). Bars, 50 µm. (B) Photomicrograph of sperm from the epididymides of wild-type and nectin-3–/– mice. Mutant sperm have nuclei with irregular shapes. Bars, 10 µm. The results shown are representative of three independent experiments.

 
Inability of nectin-2 to localize at Sertoli–spermatid junctions in the nectin-3–/– mice testes

We have previously shown that nectin-2 and nectin-3 asymmetrically localize at the Sertoli cell side and at the spermatid side of Sertoli–spermatid junctions, respectively, and that the localization of nectin-3 depends on the presence of nectin-2 (Ozaki-Kuroda et al. 2002). We then examined whether the localization of nectin-2 at Sertoli–spermatid junctions also depends on the presence of nectin-3. Nectin-2 and nectin-3 co-localized with F-actin at Sertoli–spermatid junctions which were found at the adluminal compartment of the seminiferous tubules in the wild-type testes as described (Fig. 2, Nectin-2, Nectin-3; arrows). Unlike nectin-3, the signal for nectin-2 was also observed at Sertoli–Sertoli junctions which were found at the basal compartment of the seminiferous tubules (Fig. 2, Nectin-2; arrowheads). In the nectin-3–/– testes, the signal for nectin-3 was undetectable and the signal for nectin-2 disappeared at Sertoli–spermatid junctions (Fig. 2, Nectin-2; arrows), whereas the signal for nectin-2 appeared to be restored at the Sertoli–Sertoli junctions (Fig. 2, Nectin-2; arrowheads). The signal for F-actin was disorganized in the nectin-3–/– testes (Fig. 2; F-Actin; arrows). These results indicate that the presence of nectin-3 is essential for the localization of nectin-2 at Sertoli–spermatid junctions but not at Sertoli–Sertoli junctions.


Figure 2
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  		Figure 2  Localization of nectins at Sertoli–spermatid junctions in the testes of nectin-3+/– and nectin-3–/– mice. Frozen sections of the testes of adult mice were subjected to immunofluorescence microscopy. +/– nectin-3+/– mice; –/– nectin-3–/– mice; Arrows, Sertoli–spermatid junctions; Arrowheads, Sertoli–Sertoli junctions. Bars, 20 µm. Sertoli–spermatid junctions and Sertoli–Sertoli junctions were recognized based on the F-actin staining, the location in the seminiferous tubules, and the nuclear morphology. The basement membranes of the seminiferous tubules are located on the bottom side in all images. The results shown are representative of three independent experiments.

 
Disorganized structure of Sertoli–spermatid junctions in the nectin-3–/– mice testes

The structure of Sertoli–spermatid junctions in the nectin-3–/– testes was further examined by transmission electron microscopy. In the wild-type seminiferous tubules, the acrosome-facing surface of elongated spermatid heads was tightly attached to Sertoli cells and was continuously covered by the striated band of parallel F-actin bundles (Fig. 3, Wild-type). However, spermatids detached from Sertoli cells in the nectin-3–/– testes (Fig. 3, Nectin-3–/–). This phenotype of the nectin-3–/– mice is indistinguishable from that of the nectin-2–/– mice (Bouchard et al. 2000; Ozaki-Kuroda et al. 2002; Mueller et al. 2003).


Figure 3
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  		Figure 3  Ultrastructure of Sertoli–spermatid junctions in the testes of nectin-3–/– mice. The elongated spermatids of the wild-type and the nectin-3–/– mice observed by transmission electron microscopy. A, acrosomes; N, nuclei of spermatids; S, Sertoli cells. Bars, 1 µm.

 
Restoration of the testicular phenotype of the nectin-3–/– mice by transplantation of wild-type spermatogenic stem cells

To examine whether nectin-3 localizes at the spermatid side of Sertoli–spermatid junctions and heterophilically trans-interacts with nectin-2 in Sertoli cells, transplantation experiments of spermatogenic stem cells (spermatogonia) were performed (Fig. 4). In the nectin-3–/– testes, nuclei of spermatids showed irregular shapes and the signal for F-actin around the spermatid heads was disorganized (Figs 2 and 4, upper column). On the other hand, wild-type spermatogonia, expressing EGFP in acrosome transplanted into the nectin-3–/– testes, differentiated into spermatids that were comparable to the wild-type spermatids with regard to all the morphological aspects described above (Fig. 4 lower column). Thus, the presence of nectin-3 in spermatids as well as nectin-2 in Sertoli cells was sufficient to restore the proper organization of Sertoli–spermatid junctions and spermatid differentiation in the nectin-3–/– testes.


Figure 4
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  		Figure 4  Transplantation of spermatogenic stem cells using the testes of nectin-3–/– mice. Three pairs of recipient nectin-3+/– or nectin-3–/– mice were depleted for endogenous spermatogenesis and were transplanted with spermatogonia carrying EGFP transgenes. The frozen sections of testes were doubly stained with phalloidin and DAPI. Upper column, the testis of nectin-3–/– mice. Lower column, the testis of nectin-3–/– mice that is transplanted with spermatogonia. Arrowheads, spermatids with an irregular shape; Arrows, spermatids with a normal shape. Bars, 10 µm.

 

   Discussion
Top
 Abstract
 Introduction
 Results
 Discussion
Experimental procedures
 References
 
We have characterized here the nectin-3–/– mice and found that these mice show male-specific infertility and defects in the later steps of sperm morphogenesis, exhibiting distorted nuclei and abnormal distribution of mitochondria. These testicular phenotypes of the nectin-3–/– mice are indistinguishable from those of the nectin-2–/– mice (Bouchard et al. 2000; Ozaki-Kuroda et al. 2002; Mueller et al. 2003). Consistent with the previous findings that nectin-2 and nectin-3 co-localize at Sertoli–spermatid junctions and that the localization of nectin-3 is disorganized in the nectin-2–/– mice (Ozaki-Kuroda et al. 2002), the localization of nectin-2 is disorganized in the nectin-3–/– mice. We have also shown here that transplantation of wild-type spermatogenic stem cells rescues the defects in the sperm morphogenesis of the nectin-3–/– mice although transplantation of wild-type spermatogenic stem cells was reportedly unable to rescue the defects in the sperm morphogenesis of the nectin-2–/– mice. On the other hand, transplantation of spermatogonia prepared from nectin-2–/– mice to the testis of W/Wv mutant mice, which lacks endogenous spermatogenesis, confers formation of normal spermatids without the nectin-2 gene (Ozaki-Kuroda et al. 2002). Taken together, these results indicate that the heterophilic trans-interaction between nectin-2 in Sertoli cells and nectin-3 in spermatids is essential for the formation and maintenance of Sertoli–spermatid junctions that plays a critical role in spermatid development.

It should be noted that the signal for nectin-2 at Sertoli–spermatid junctions completely disappears in the nectin-3–/– testes, while the signal for nectin-3 is disorganized but still remains in the nectin-2–/– testes. Considering the signal for nectin-2 at Sertoli–Sertoli junctions remains in the nectin-3–/– testes, it is likely that nectin-3 in spermatids heterophilically trans-interacts with CAM(s) other than nectin-2 in Sertoli cells. Nectin-3 forms hetero-trans-dimers not only with nectin-1 and nectin-2 but also with other Ig-like CAMs, nectin-like molecules (Necl)-1, Necl-2 and Necl-5 (Takai et al. 2003). Among these CAMs, nectin-1 is scarcely expressed in the testes (Satoh-Horikawa et al. 2000), while Necl-2, also known as SgIGSF/TSLC-1, is expressed in spermatids but not in Sertoli cells (Wakayama et al. 2003). Although it remains unknown which CAMs other than nectin-2 in Sertoli cells heterophilically trans-interact with nectin-3 in spermatids, such interactions might be not so important as those between nectin-2 and nectin-3.

Recent studies have suggested that the cadherin-catenin system localizes at Sertoli–spermatid junctions (Cheng & Mruk 2002). However, it remains unknown whether the cadherin-catenin system is essential for the formation of Sertoli–spermatid junctions. In contrast, the nectin-afadin system is now established to be essential for the formation of Sertoli–spermatid junctions. We have shown that the trans-interaction of nectins recruits cadherins to the nectin-based cell-cell adhesion sites through afadin and catenins during the formation of AJs in epithelial cells and fibroblasts in culture (Takai et al. 2003; Takai & Nakanishi 2003). If this concept is extended to the formation of Sertoli–spermatid junctions, the heterophilic trans-interaction of nectin-2 and nectin-3 would first form the cell adhesion, then recruit N-cadherin to the nectin-based adhesion sites, and finally end up establishing the strong adhesion undercoated with F-actin that is mediated by afadin and catenins at Sertoli–spermatid junctions.

JAM-C is reportedly required for the differentiation of round spermatids into spermatozoa (Gliki et al. 2004). JAM-C–/– male mice are infertile and fail to produce mature sperms. Interestingly, similar to nectin-2 and nectin-3, JAM-C in spermatids heterophilically trans-interacts with JAM-B in Sertoli cells. Disorganization of the actin cytoskeleton is also observed in JAM-C–/– male mice. It remains unknown whether JAM-B is also essential for spermatid development. Thus, multiple heterophilic trans-interactions of Ig-like CAMs appear to be required for spermatid development. We have shown that the trans-interactions of nectins recruit JAM-A to the nectin-based cell-cell adhesion sites through afadin and ZO-1 in epithelial cells and fibroblasts in culture (Takai et al. 2003; Takai & Nakanishi 2003). Therefore, the heterophilic trans-interaction of nectin-2 and nectin-3 might recruit JAM-B and JAM-C to the nectin-based adhesion sites at Sertoli–spermatid junctions. It has also been reported that JAM-C co-localizes with a cell polarity complex, consisting of Cdc42, Par-6 and aPKC at Sertoli–spermatid junctions and that JAM-C is necessary for the assembly of this cell polarity complex (Gliki et al. 2004). Since the trans-interaction of nectins induces activation of Cdc42 and Rac small G proteins and nectin-3 directly binds Par-3 (Takai et al. 2003), Cdc42 activated by nectins is likely to induce the polarity protein complex formation and spermatid development.


   Experimental procedures
Top
 Abstract
 Introduction
 Results
 Discussion
 Experimental procedures
References
 
Animals

The animals and procedures used in this study were in accordance with the guidelines and approval of Osaka University Medical School Animal Care and Use Committee. Nectin-3–/– mice were generated as described (Inagaki et al. 2005). Transgenic mice (C57BL/6TgN[acro/act-EGFP]OsbN01) carrying both acrosin/EGFP and pCXN-EGFP transgenes were generated as described (Ohta et al. 2000a).

Antibodies

Rat anti-nectin-2 and anti-nectin-3 monoclonal antibodies (mAbs), which recognize the extracellular regions of nectin-2 (#502–57) and nectin-3 (#103-A1), respectively, were prepared as described (Takahashi et al. 1999; Satoh-Horikawa et al. 2000; Mizoguchi et al. 2002).

Histological analysis and immunofluorescence microscopy

For histological analysis, adult mouse testes were dissected and fixed overnight at 4 °C by Bouin's fixative, rinsed with 70% ethanol, dehydrated in graded alcohols, embedded in paraffin, sectioned at 4 µm, and stained with hematoxylin and eosin. For immunofluorescence microscopy, frozen sections were prepared as described (Inagaki et al. 2003), with some modifications. Briefly, 10-µm thick frozen sections of adult mouse testes were fixed with 99% ethanol at –20 °C for 30 min and then with 100% acetone at 4 °C for 1 min. The samples were then washed, incubated with the appropriate primary Ab(s), washed, and incubated with the appropriate fluorophore-conjugated secondary Abs, 4-,6-diamidino-2-phenylindole dihydrochloride (DAPI) (Nakarai) and/or rhodamine-conjugated phalloidin (Molecular Probe). The samples were observed with a Radiance 2100 confocal laser scanning microscope (Bio-Rad, Hercules, CA, USA). The tissue organization of testes was better preserved by the method described above than by the conventional perfusion fixation method. However, for transplantation assay of spermatogenic stem cells, whole-body perfusion with 4% paraformaldehyde was applied to mice before the dissection of the testes. Unless otherwise specified, the apical-to-basal axis of the seminiferous tubules corresponds to the top-to-bottom axis of the photographs in the higher magnification. The stage of each tubule was determined by DAPI staining.

Transmission electron microscopy

The testes of adult mice were fixed with 2% glutaraldehyde in 0.1 M cacodylate buffer at 4 °C. They were washed with 0.1 M cacodylate buffer, and refixed with the 2% osmium tetroxide. They were dehydrated by passage through a graded series of ethanol and propylene oxide, and embedded in epoxy resin. From this sample, 70–80-nm ultrathin sections were cut and doubly contrasted with uranyl acetate and lead staining solution. They were observed with a JEOL JEM-2000EX electron microscope (JEOL).

Transplantation of spermatogenic stem cells

Transgenic mice (C57BL/6TgN[acro/act-EGFP]OsbN01) carrying both acrosin/EGFP and pCXN-EGFP transgenes were described (Ohta et al. 2000a). To deplete endogenous spermatogenesis, recipient nectin-3+/– or nectin-3–/– littermates were injected intraperitoneally with 40 mg/kg busulfan for 4 weeks before the transplantation. Donor cell preparation and transplantation via the efferent ductules were performed (Ohta et al. 2000b). A total of 12 weeks after the operation, recipient testes were dissected and were analyzed by immunofluorescent microscopy as described above. In this experiment, three pairs of littermates of nectin-3+/– and nectin-3–/– mice were used as recipients. Although the transplantation efficiency (the number of colonized tubules/number of total tubules in a testicular section) varies in each testis, morphological features of colonized tubules were identical within each experimental group.


   Acknowledgements
 
We thank Drs M. Okabe, A. Isotani, and H. Tanaka (Genome Information Research Center, Osaka University) for sperm movement analysis, transplantation experiments of spermatogenic stem cells, helpful discussions, and critical readings of the manuscript. The investigation at Osaka University Medical School was supported by grants-in-aid for Scientific Research and for Cancer Research from the Ministry of Education, Culture, Sports, Science & Technology of Japan (2004, 2005).


   Footnotes
 
Communicated by: Eisuke Nishida

* Correspondence: E-mail: ytakai{at}molbio.med.osaka-u.ac.jp


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 Abstract
 Introduction
 Results
 Discussion
 Experimental procedures
 References
 
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Received: 25 May 2006
Accepted: 19 June 2006




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