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From the * Department of Anatomy and Cell Biology,
McGill University, Montréal, Canada;
INRS-Institut Armand-Frappier,
Université du Québec, Pointe-Claire, Canada;
Department of Genetics and Tumor Cell Biology,
St Jude Children's Research Hospital, Memphis, Tennessee; and
Département de Stomatologie,
Université de Montréal, Montréal, Canada.
| Correspondence to: Dr Louis Hermo, McGill University, Department of Anatomy and Cell Biology, 3640 University Street, Montréal, Québec, Canada, H3A 2B2 (e-mail: louis.hermo{at}mcgill.ca). |
| Received for publication April 5, 2007; accepted for publication May 21, 2007. |
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Abstract |
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Key words: Epididymis, principal cells, sperm counts, lanthanum nitrate, claudins
-neuraminidase and ß-galactosidase
(d'Azzo et al, 1982;
Galjart et al, 1991). PPCA has
2 functions. First, it facilitates the intracellular routing, lysosomal
targeting, andactivationof -neuraminidase, and second, it protects both
ß-galactosidase and -neuraminidase against rapid proteolytic
degradation inside lysosomes (d'Azzo et
al, 1982; Galjart et al,
1991; Zhou et al,
1996; van der Spoel et al,
1998). PPCA is sorted to lysosomes as a 54-kd precursor protein
via the mannose-6-phosphate receptor–mediated pathway, where it is
processed into its mature 32/20-kd, disulfide-linked 2-chain form
(Jackman et al, 1992;
Hanna et al, 1994;
Itoh et al, 1995;
Rottier et al, 1998). The
creation of a mouse model deficient in PPCA allowed a means to investigate the
importance of this enzyme in a wide variety of cells and tissues of the body.
The absence of PPCA leads to the storage of sialylated oligosaccharides and
glycopeptides within lysosomes and their accumulation in a wide variety of
cells and tissues of the body (van Pelt et
al, 1988; d'Azzo et al,
1995; Zhou et al,
1995; Sohma et al,
1999), in addition to epithelial cells of the testis and
epididymis (Korah et al,
2003a,
b). Proper maturation of sperm (ie, acquisition of motility and fertility) occurs as these cells transit through the proximal region of the epididymis, and this is accomplished by the segment-specific activities of the epithelial cells lining this duct (Orgebin-Crist and Olson, 1984; Cornwall et al, 2002; Robaire et al, 2006). The epididymis in many mammals is composed of principal, clear, basal, narrow, and apical cells, all of which contribute to fine-tuning the luminal environment to create the proper environment necessary for sperm maturation (Hamilton, 1975; Orgebin-Crist et al, 1975). These epithelial cells monitor proper water balance, ionic composition, and pH of the lumen and perform activities such as secretion and endocytosis of proteins and protection and transportation of sperm (Robaire and Hermo, 1988; Hermo and Robaire, 2002; Breton, 2003). The number of epididymal proteins implicated in these various processes continues to grow, which attests to the marked diversity and complexity of this tissue (Robaire et al, 2006). Thus, alterations in the expression of proteins of these cellular activities will have an effect on the structure and functions of the epididymal epithelium, which could impact sperm maturation.
The epididymis of PPCA –/– mice develops major structural alterations in principal, clear, narrow, and basal cells of the epithelium with the caput and corpus regions being the most dramatically affected (Korah et al, 2003b). Notable are the accumulation of pale lysosomes within the cytoplasm of these cells, often overwhelming the other organelles. Quantitative analyses have confirmed that outer profile areas of epididymal tubules in caput and corpus regions of PPCA –/– mice are increased in size compared with controls. This is associated with a significant increase in the size of the epithelium with a concomitant decrease in luminal profile area, both suggestive of a swollen epithelial lining (Korah et al, 2003b). Sperm are found in the epididymal lumen; PPCA –/– mice are fertile, but their fertility status, based on preliminary counts of pups per litter, appears to decline with age (d'Azzo, unpublished data). Another prominent feature of PPCA –/– mice is the accumulation of macrophages within the intertubular spaces of the epididymis. These cells are engorged with pale lysosomes, reflecting the absence of PPCA in their lysosomes (Korah et al, 2003b). The presence of these cells, as well as intraepithelial halo cells that are also grossly altered, suggests that antigens may be leaking from the epididymal lumen as a result of improper functioning of the blood-epididymal barrier.
The blood-epididymal barrier is formed by the presence of a complex number of apical tight junctions and adherens junctions between adjacent epithelial cells (Cyr et al, 2002). Claudins (Cldns) are a large family of at least 24 transmembrane proteins which have been shown to be essential for the structural integrity of tight junctions (Furuse et al, 1998; Morita et al, 1999; Sonoda et al, 1999; Tsukita and Furuse, 2000; Guan et al, 2005). Recent studies have shown that occludin and Cldns are prominent components of tight junctions between epididymal epithelial cells (Cyr et al, 1999; Gregory et al, 2001; Guan et al, 2005; Gregory and Cyr, 2006).
In the present study, the effects of PPCA deficiency on the integrity of the blood-epididymal barrier and functions of the epididymal epithelium were assessed using lanthanum nitrate as a tracer to monitor the barrier integrity and light microscopy (LM) immunocytochemistry to characterize differences in the expression of 4 members of the Cldn family of tight junction–sealing proteins. Part of the effectiveness of epididymal functions was evaluated by indirectly characterizing the motility characteristics of sperm taken from the cauda epididymides of PPCA-deficient mice.
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Materials and Methods |
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Primary antibodies used in this study (summarized in Table 1) included: 1) rabbit anti–Cldn-1 (51-9000; Zymed Laboratories, South San Francisco, Calif; 1:50 dilution), 2) rabbit anti–Cldn-3 (34-1700; Zymed Laboratories; 1:50 dilution), 3) rabbit anti–Cldn-8 (GTX77832; Gene Tex Inc, San Antonio, Tex; 1:100 dilution), and 4) rabbit anti–Cldn-10 (ab24792; Abcam Inc, Cambridge, Mass; 1:100 dilution). Dilution buffer was purchased from DakoCytomation (S0809; Mississauga, Canada). Sections of Bouin- and St Marie–fixed epididymides were deparaffinized with Histoclear (Fisher Scientific Company, Ottawa, Canada) and rehydrated in a series of 100%, 100%, 95%, 80%, 70%, and 50% ethanol solutions, 0.3 M glycine, and 1 x phosphate-buffered saline. Antigen retrieval was accomplished by boiling the sections in a microwave at full power for 2 to 3 minutes in 0.1 M citrate buffer (pH 6.0), followed by heating for 7 minutes at 60% power of the microwave. Endogenous peroxidase activity was blocked for 5 to 10 minutes with a peroxidase-blocking reagent (DakoCytomation), followed by washing. Immunolocalization of Cldns was performed using the Envision+ peroxidase diaminobenzidine (DAB) kit (K4010; DakoCytomation). Washings between each step were conducted for 10 minutes using a buffer solution containing 0.05 M Tris, 0.3 M NaCl, and 0.1% Tween 20 (pH 7.2–7.6). Substrate-chromogen solutions were prepared by adding 24 µL of liquid DAB + chromogen to 1 mL of the substrate buffer. The sections were counterstained for 10 seconds in a 1:5 diluted solution of 0.1% methylene blue and 0.1% thionin, washed, and quickly dehydrated with Histoclear. Coverslips were mounted on slides with Permount. Controls consisted of treating the sections with normal rabbit serum at a dilution similar to that of the primary antibody. All digital images were taken with an Infinity USB 2.0 Hi-Speed camera (Lumenera Scientific, Ottawa, Canada).
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Pearson r for parameter A across parameters A–N in PPCA
–/– mice) – (Pearson r for parameter A
across parameters A–N in PPCA +/+ control mice). Principal component
analyses of covariances were computed with scaled data using the multivariate
statistical package (version 3.1; Kovach Computing Services, Pentraeth, United
Kingdom).
Sperm Counts
The frozen left cauda epididymidis of each animal was thawed and
homogenized in a 50-mL conical tube containing 1 mL of distilled water. The
tissue was then homogenized on ice for 1 to 2 minutes with a Polytron. A
100-µL aliquot of the resulting homogenate was placed in a 1.5-mL
microcentrifuge tube coated with IDENT fluorescent dye (Hamilton Thorne
Biosciences) and incubated for 5 to 10 minutes at room temperature. The
solution was mixed, and a 5-µL aliquot was placed in a 20-µm sperm
analysis chamber (2 Cel; Hamilton Thorne Biosciences) and quantified with the
IVOS semen analyzer under ultraviolet light using the IDENT option/static
sperm. Log10 transformations were done prior to carrying out
t-tests assuming unequal variances; P < .05 was
considered significant.
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Results |
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Immunolocalization of Cldns 1, 3, 8, and 10 indicated that while their expression in PPCA –/– mice was not abolished, dramatic changes in their localization were evident. Immunoreactions were defined as apical, lateral, basal, and cytoplasmic (Table 1). Apical membrane reactions typical of PPCA +/+ mice in all regions (Table 1; Figure 2a, c, e, and f) were diminished or focalized to apical cytoplasmic reactions in most regions in PPCA –/– mice (Table 1; Figure 2b, d, f, and h) in the case of Cldn 1. Cldn 3 exhibited apical and lateral immunoreactions between adjacent principal cells in the initial segment and caput regions of PPCA +/+ mice (Figure 3a and c). The immunoreactions were decreased in the initial segment of PPCA –/– mice (Figure 3b), and Cldn 3 was localized to the cytoplasm of principal cells of the caput region (Table 1; Figure 3d). Other regions showed no differences between PPCA +/+ and PPCA –/– mice (Table 1; Figure 3e and f). Apical and basal membrane immunoreactions of Cldn 8 in PPCA +/+ mice were reduced in the caput and corpus regions of PPCA –/– mice (Table 1; Figure 4a through f). For Cldn 10 (Figure 5a through f), the caput and corpus regions showed no apical membrane staining in PPCA –/– mice (Figure 5b and d compared with Figure 5a and c). However, similar immunoreactions were noted in the cauda region between wild-type and PPCA –/– mice (Figure 5a and c compared with Figure 5e and f). Negative control sections incubated without primary antibody showed no immunoreaction anywhere within the epididymis (Figure 4g and h).
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Discussion |
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Movement of material across cell membranes occurs in an energy-dependent manner through a large number of cell-specific pumps, channels, and transporters. Recent studies have shown that tight junctions regulate solute movement through the paracellular pathway across epithelia (van Itallie and Anderson, 2006). Paracellular barriers vary among epithelia and behave as if they are lined with pores that have charge and size selectivity. Cldns are transmembrane proteins that are essential for the structural integrity of tight junctions (Furuse et al, 1998; Sonoda et al, 1999; Morita et al, 1999; Tsukita and Furuse, 2000; Guan et al, 2005). They are intercellular adhesion molecules that have variable pore-like properties (van Itallie and Anderson, 2006). This appears to be accomplished by the presence of charged amino acids located in the extracellular loops of several Cldns that establish paracellular charge selectivity (Colegio et al, 2002; van Itallie et al, 2003). The presence of Cldns 1 and 2 has been proposed to constitute aqueous pores with high conductance (Furuse et al, 2001). Cldn 10 appears to form anion-selective channels in tight junctions of the rat epididymis (Guan et al, 2005). In the present study, the altered states of several Cldns in PPCA –/– mice suggest that the ion composition of the epididymal lumen may be altered and in this way adversely affect sperm maturation as reflected by altered motility and sperm shape parameters. Indeed, it has been shown that altering the epididymal lumen pH can affect sperm motility (Morton et al, 1974; Turner and Howards, 1978; Pholpramool and Chaturapanich, 1979; Wong et al, 1981). Also, changes in sperm cell volume have been reported for c-Ros–deficient mice that appear to affect several osmolyte transporters (Cooper et al, 2003).
Cldns have been reported in rat epididymis where they show both regional specificity and preferences for either apical, lateral, or basolateral locations on epididymal epithelial cell membranes (Gregory et al, 2001; Guan et al, 2005; Gregory and Cyr, 2006). In the present study, we clearly showed that each of the 4 Cldn family members investigated, which had not previously been localized in mice, showed the same varied immunostaining patterns in principal cells depending on the epididymal region and differences in specific Cldns similar to what was previously described for rat. Apical reactions for Cldns 1 and 3, however, showed plasma membrane immunolocalization in the mouse that were different from those reported for rat (Gregory et al, 2001; Gregory and Cyr, 2006). This suggests that there may be some species variability in proteins associated with junctional complexes in the epididymis between rats and mice.
The distributions of Cldns were dramatically different in PPCA –/– mice compared with wild-type mice (Table 1; Figures 2, 3, 4, 5). In some cases, there was a reduction or complete absence of immunostaining along the apical plasma membranes, where the blood barrier resides, complemented by diffuse apical cytoplasmic reactions. Other plasma membrane domains were only affected in certain epididymal regions and differed depending upon a given Cldn. The presence of apical cytoplasmic reactions suggests that targeting of the respective tight junction protein is compromised in PPCA –/– mice. Apical reactions have been documented for several Cldns during postnatal epididymal development (Guan et al, 2005; Gregory and Cyr, 2006). In the present study, approximately 40% of the tubules were noted to be compromised by administration of lanthanum nitrate, and while we did not perform quantitative analyses, most of these changes were noted in more proximal regions of the epididymis. This suggests that permeability of lanthanum nitrate in the cauda region may be different in PPCA –/– mice and may explain the difference noted for Cldn staining in this region. Indeed, in PPCA –/– mice, the cauda epididymis was noted to be the least affected region of the epididymis in terms of structural abnormalities (Korah et al, 2003b). Whereas we do not know the precise mechanism underlying the link between PPCA –/– deficiency and the altered blood-epididymal barrier, we suggest that the accumulation of lysosomes in both number and size in epithelial cells, which at times completely fills their entire cytoplasm, could compromise other organelles such as the endoplasmic reticulum and Golgi apparatus. This compromise would lead to a decrease in the synthesis of proteins, including those involved in junctional complexes.
In the proximal epididymal regions of most mammals, including the mouse, sperm undergo maturation by acquiring motility and the ability to fertilize the ovum (Orgebin-Crist and Olson, 1984). The acquisition of sperm motility involves quantitative increases in the percentage of motile sperm as well as qualitative differences in their motility behavior (Blandau and Rumery, 1964; Hinton et al, 1979; Cornwall et al, 1986; Soler et al, 1994). The epithelial cells of the proximal epididymis fine-tune the luminal environment in which sperm mature by providing the proper protein and lipid components that interact with the sperm surface to render them mature and by creating the proper pH and ionic and water balance (Cyr et al, 2002). Thus, the integrity of the structure and functions of these cells is an essential prerequisite for proper sperm maturation. The compromised nature of principal cells within the caput and corpus regions of PPCA –/– mice as indicated by leakiness to lanthanum nitrate and altered expression of the 4 Cldns suggests that cells in these regions have diminished functions; this is likely to be reflected as incomplete or improper maturation of sperm. Indeed, numerous macrophages were noted in the epididymal intertubular spaces, suggesting a response to antigens emanating from the lumen, some of which could be derived from sperm. The former may secrete factors in response to these antigens that could enter the lumen, thereby affecting the sperm themselves and their motility behavior.
The results from the motility analyses (Table 2) fully support the idea that sperm maturation is compromised, as indicated by the extreme shift from the motile (and progressively motile) category to the static category for the much reduced numbers of sperm that actually are produced in the PPCA –/– mice. It should be noted that sperm emanating from the testis do not show any signs of structural abnormalities and appear to be comparable to controls, as seen in the electron microscope (Korah et al, 2003a). The present results further show unequivocally that the shift of motility involves sperm from primarily the rapid category and likely to a lesser extent, based on Figure 6, the medium and slow categories in the more severely affected mice. It is also not surprising that differences within the percent medium and slow categories, despite their large differences in relative percent change (–30% vs 100%, respectively), could not be resolved as significant. Indeed, the absolute differences they represent are actually quite small (–11% and 2.7% of total sperm in PPCA –/– mice), and as ratio values, they would therefore require large numbers of observations in controls and especially the experimental groups to be established as significant.
Sperm velocity parameters VAP and VSL were modestly, albeit significantly, depressed, whereas the parameter track velocity (VCL) was unchanged in PPCA –/– mice (Table 2). VCL represents the average velocity over each individual step that a sperm makes while moving. The fact that it remains equal to normal while the velocity calculated between the starting and ending points of the sperm track (VSL) and the velocity computed as an average over all steps in a sperm track (VAP) are shorter suggest that sperm in PPCA –/– mice exert more effort moving side to side than moving forward in space. This conclusion is supported by the findings of a 61% reduction in sperm progressive velocity and much higher BCF and ALH values in the PPCA –/– mice (more center path crossing and thrashing of sperm heads side to side; Table 2). These are all symptomatic of less vigorous sperm being produced in PPCA –/– mice.
Summed correlation difference plots identified 5 motility parameters that
appear to stand out more prominently from other parameters in PPCA
–/– mice (Figure
7A). These were elongation, BCF, and percent medium, slow, and
static sperm (Figure 7A).
Elongation, BCF, and percent static sperm in this plot showed increasing
magnitudes in mean differences to wild-type mice, but they all shared a
similar level of summed correlation differences that is decidedly more
negative than the majority of other motility parameters
(Figure 7A). Percent slow sperm
differed from the majority of motility parameters only as a result of its
large relative increase in mean difference from wild-type mice, whereas
percent medium sperm showed a mean difference that is slightly negative but
within range of other motility parameters and a summed correlation difference
that is more positive compared with all other parameters. The same 5 motility
parameters were also found to be prominent and arrayed graphically in similar,
although not identical, fashion in knockout mice lacking estrogen receptor
(ERKO) (Ruz et al,
2006). These mice are infertile, and the root cause of their
problem appears to result from excessive water retention associated with
defective expression of transporters in the efferent ducts
(Hess, 2002). As documented in
this study, PPCA –/– mice have altered expression of Cldns in the
caput and corpus regions, making the lumens leaky and upsetting the water and
ion balance, which may resemble some of the problems encountered in the
ERKO mice.
The unexpected prominence of percent medium sperm within the data set was also confirmed by principal component analyses of covariances in which variable loadings on the first 2 main axes indicated that percent medium sperm forms a strong main component along the negative y-axis opposite the velocity parameters VCL, VSL, and VAP (Figure 7B). Case loadings done on the same principal components plot show clearly the dispersed trend for more static sperm in PPCA –/– mice and the tight trend for motile, progressive, and rapid sperm in normal PPCA +/+ mice (Figure 7B). This plot clearly shows that the velocities of sperm in PPCA –/– and PPCA +/+ mice (VCL, VSL, and VAP) are similar and independent of the number of static sperm in a given sample (Figure 7B, vertical spread of all points plotted). Hence, sperm in PPCA –/– are either static or motile, and if they are motile, then they travel with velocity features resembling, although not exactly the same, as normal mice.
Taken together, results from this study suggest that there are several cumulative root causes for fertility problems in PPCA –/– mice. First, PPCA –/– mice produced 70% fewer sperm compared with normal male mice. Second, within this diminished sperm population, only 45% of sperm were motile; of these, only 20% moved in a rapid manner. In comparative terms, this represents the equivalent of only 6% of sperm moving rapidly in PPCA –/– mice (30% production x 20% rapid = 6%) relative to the 50% of rapidly moving sperm routinely produced by wild-type mice (Table 2). Finally, motile sperm in PPCA –/– mice showed more side to side head movements and path crossings as compared with normal mice, suggesting that these sperm are less forwardly vigorous.
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Acknowledgments |
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Footnotes |
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