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Departments of Pediatrics (J.T., F.S., J.-Q.H., R.A.G.), Pharmacology and Therapeutics (J.T., F.S.), Human Genetics (J.T., F.S., J.-Q.H., R.A.G.) and Anatomy and Cell Biology (I.H.S., H.I.A., L.H.) and The McGill University-Montréal Children’s Hospital Research Institute (J.T., F.S., J.-Q.H., R.A.G.), Montréal, Québec, Canada H3H 1P3, Ludwig Institute for Cancer Research, New York Branch at Memorial Sloan-Kettering Cancer Center (S.R.F., G.R.), New York, New York 10021; Department of Molecular Biotechnology (M.G., R.A.), University of Washington, Seattle, Washington 98195
Address all correspondence and requests for reprints to: Dr. Jacquetta M. Trasler, The McGill University-Montréal Children’s Hospital Research Institute, 2300 Tupper Street, Montréal, Québec, Canada H3H 1P3. E-mail: mdja{at}musica.mcgill.ca
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit) or Hexb (ß-subunit)
genes, respectively, encoding the enzymes Hex A (structure, ß) and
Hex B (ßß). Testis weight, morphology, and sperm counts were
unaffected in Hex-deficient mice. In the epididymis of the Hex
A-deficient Hexa-/- mice, there was a large increase
in the size and number of lysosomes in the initial segment/intermediate
zone. In Hexb-/- mice (Hex A and B-deficient), the
epididymal defects were much more extensive and the cytoplasm of all
cell types throughout the efferent ducts and epididymis was filled with
pale, uncondensed, enlarged lysosomes. In contrast to the brain where
GM2 ganglioside accumulates, both mutant mice accumulated
two non-GM2 gangliosides in the epididymis. The major
accumulated species was characterized by electrospray ionization tandem
mass spectrometry. The Hexa-/- male mice were fertile;
however, litter sizes were reduced. The Hexb-/- males
were able to sire normal sized litters up to nine weeks of age and
remained healthy until 16–20 weeks of age. The extensive abnormalities
in the Hexb-/- mice, in contrast to region-specific
effects in the Hexa-/- mice, indicate an important and
novel role for the Hex B isozyme in the epididymis and a
region-specific role for Hex A in the initial segment/intermediate
zone. In contrast to other reports, our results indicate that Hex is
not essential for fertilization in young adult male mice. To explain
the extensive epididymal abnormalities in the Hexb-/-
mice, we propose that substrates for Hex, such as testis-derived
glycolipids, cannot be catabolized and accumulate in lysosomes, leading
to epididymal dysfunction and abnormalities in the epididymal luminal
environment that supports sperm maturation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and one ß-subunit; and Hex B, a homodimer of
ß-subunits.
Within the male reproductive tract, Hex has been immunolocalized to
Sertoli cells of the testis (5, 6). Hex is secreted by Sertoli cells,
along with other selected lysosomal enzymes, such as -mannosidase
and procathepsin L. The secreted lysosomal enzymes are postulated to
play a role in germ cell release from the seminiferous epithelium or to
be targeted to germ cell lysosomes or the acrosome (7, 8). By
immunocytochemistry, Hex has been localized in the mouse and rat sperm
acrosome (9, 10, 11). By biochemical assay, Hex B is the isozyme present in
mouse sperm (9). Decreases in in vitro fertilization rates
in mice, following application of a specific inhibitor of Hex,
suggested an important role for the enzyme in fertilization (9). In the
rodent epididymis, Hex activity increased over 10-fold from infancy to
sexual maturity and was androgen dependent (1). Within the epididymis,
Hex enzyme activity (10, 11), as well as - and ß-subunit messenger
RNA (mRNA) levels, were highest in the corpus region (6). Using
synthetic substrates and ion exchange chromatography to distinguish Hex
A and B in mouse tissues, Beccari et al. (3) showed that,
whereas the brain and testis contained predominantly Hex A, the
epididymis and kidney activities were almost entirely due to Hex B.
The present study was designed to gain a better understanding of the
role of Hex in reproduction by studying the testes and epididymides of
mice made deficient in Hex A through targeted disruption of the
Hexa gene (encodes the Hex -subunit) or in Hex A and Hex
B through disruption of the Hexb gene (encodes the Hex
ß-subunit). The Hexa-/- mice (Hex A-deficient)
accumulate GM2 ganglioside in the CNS but otherwise remain
healthy until over one year of age (12). The Hexb-/- mice
(Hex A- and Hex B-deficient) show higher ganglioside accumulation, both
centrally and peripherally, develop progressive weakness and die at
5–6 months of age (12). Similar phenotypes in Hex-deficient mice have
been reported by Sango and colleagues (13) and Cohen-Tannoudji and
colleagues (14). The availability of the two mouse models provides an
opportunity to study the reproductive consequences of Hex deficiency as
well as to compare the different roles of Hex A and Hex B in
reproduction. The results reveal major lysosomal abnormalities
restricted to the initial segment and intermediate zone of the
epididymis in the Hexa-/- mice; in contrast, extensive
abnormalities were found throughout the efferent ducts and epididymis
of the Hexb-/- mice. The contrasting phenotypes in the two
models suggest an essential role for Hex in the efferent ducts and
epididymis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-subunit) or
Hexb (ß-subunit) genes has been reported (12).
Heterozygotes were interbred to produce homozygous (-/-),
heterozygous (-/+) and wild-type (+/+) mice. Mice were genotyped by
PCR analysis of tail DNA as previously described (12). Organ weights and sperm counts were determined on 3-month-old mice (n = 4 per genotype) to assess the effect of Hex deficiency on the male reproductive system. Testes and epididymides (divided into initial segment including the intermediate zone, caput, corpus, and cauda regions) were removed and weighed. One testis from each mouse was homogenized (Polytron, Brinkman Instruments, Ontario, Canada) for two 15-sec periods separated by a 30-sec interval in 0.9% NaCl, 0.1% merthiolate, and 0.5% Triton X-100, and spermatozoal heads were counted hemocytometrically (15).
Light and electron microscopy and immunocytochemistry
For light and electron microscopy, three mice of each of
wild-type Hexa+/+ (3 and 5 months of age),
Hexa-/- (3 and 5 months), wild-type Hexb+/+ (3
months) and Hexb-/- (3 months) were anesthetized with
sodium pentobarbital (Somnitol, MTC Pharmaceuticals, Hamilton, Ontario,
Canada). The mice were perfused-fixed through the heart with 2.5%
glutaraldehyde, buffered with 0.1 M sodium cacodylate (pH
7.4) containing 0.05% calcium chloride. After perfusion, the testes,
efferent ducts, and epididymides of the three mice from each group were
cut into approximately 1 mm3 pieces. Each epididymis was
divided into the initial segment, intermediate zone, caput, corpus, and
cauda regions. The tissue was placed in fixative for 2 h at 4 C,
rinsed three times with 0.1 M sodium cacodylate buffer
containing 0.2 M sucrose, and left in this buffer overnight
at 4 C. The tissues were subsequently rinsed in buffer and postfixed in
2% aqueous osmium tetroxide and 3% aqueous potassium ferrocyanide in
a 1:1 mixture for 2 h at 4 C. They were then rinsed in buffer,
dehydrated through a graded series of ethanol followed by propylene
oxide, and embedded in Epon. Thick sections (0.5 µm) of the testes,
efferent ducts, and various epididymal regions were cut, stained with
toluidine blue for 2 min, and observed under the light microscope. Thin
sections of selected regions of each block were cut with a diamond
knife, placed on copper grids, stained with uranyl acetate and lead
citrate, and examined with Philips 301 and 400 electron
microscopes.
For electron microscope immunocytochemistry, two anesthetized Hexb-/- mice were perfused through the heart with 0.5% glutaraldehyde combined with 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.4) containing 50 mM lysine. After removal of the epididymis, the regions were delineated as above and were immersed for 2 h in fixative at 4 C, washed two to three times in 0.15 M PBS containing 4% sucrose (pH 7.4), and then treated with PBS containing 4% sucrose and ammonium chloride for 1 h at 4 C. The tissue was subsequently washed, dehydrated in graded methanol up to 90%, and embedded in Lowicryl as described previously (6). Thick sections were cut, and selected areas of the block containing principal cells were chosen. Ultrathin sections were mounted on 300-mesh, formvar-coated nickel grids and treated for electron microscope immunolocalization (6). The grids were incubated for 30 min on a 20 µl drop of rabbit antisulfated glycoprotein-1 (SGP-1) antibody (a gift of Dr. M. Griswold, 16) diluted at 1:20 in 20 mM Tris-HCl saline containing 0.1% BSA (pH 7.4). Normal rabbit serum served as control at a dilution of 1:20.
Extraction and analysis of gangliosides
Methods for ganglioside extraction and analysis have been
described previously (16, 17). Gangliosides were purified from entire
epididymides (
0.1 g wet weight). Ganglioside GM2 was
identified by immune TLC using the anti-GM2 monoclonal
antibodies KM966 (5 µg IgG/ml; 18) and 45.66 (supernatant 1:10
diluted; 19) and purified bovine brain GM2 (Alexis Corp.,
San Diego, CA) as standards. For the initial characterization of
unknown gangliosides accumulating in the Hex-deficient mice, antibodies
R24 against GD3 (20) and 3F8 against GD2 (21)
were used.
Electrospray ionization mass spectrometry
The HPTLC purified ganglioside sample was methylated according
to the procedure described by Reinhold et al. (22) and
mass-analyzed on a TSQ-7000 mass spectrometer (Finnigan MAT, San Jose,
CA). The sample was dissolved in 100% methanol containing 5
mM ammonium acetate and infused into the mass spectrometer
at 1 µl/min by a Harvard syringe pump. The voltage for electrospray
ionization was 3.5 kV. For collisional-induced dissociation (CID)
studies, singly charged molecular ions were selected and underwent
collisions with argon gas at 3.5 mtorr at kinetic energy of 55 eV.
Fertility of ß-hexosaminidase-deficient mice
Fertility and litter sizes were assessed by retrospective
analysis of breeding records over an 18-month period. For the most
part, breeding between male and female heterozygotes was used to
generate wild-type, heterozygous, and homozygous mice for both mutants
to supply the colony. Over the 18-month period, Hexa+/-
males produced 44 litters, and Hexb+/- males produced 44
litters; males ranged in age from 6 weeks to 12 months. Occasionally,
homozygous males of each mutant strain were used for breeding;
Hexa-/- males (aged 6 weeks to 6 months) produced 14
litters and Hexb-/- males (aged 6–9 weeks) produced 11
litters. Before the onset of symptoms, six Hexb-/- males
(aged 10–12 weeks) were housed for 1 week with two females each.
Statistical analysis
Effects of Hex deficiency on sperm counts, organ weights, and
litter sizes were analyzed by one-way ANOVA followed by Duncan’s
multiple range test (23). The level of significance was taken as
P 
0.05 throughout.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. Testis weight and testicular sperm
numbers also did not differ significantly from wild-type values in the
Hexb+/- or the Hexb-/- mice. These data
suggest that sperm production was not affected significantly in either
mutant Hex-deficient mice. In contrast, total epididymal weight was
significantly higher (1.3-fold) in Hexb-/- mice than in
age-matched wild-type controls. In addition, epididymal region-specific
effects were evident with weight increases in the caput and corpus but
not in the initial segment and cauda regions compared with wild-type
mice.
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By light microscopy, the nonciliated cells of the efferent ducts of
Hexa+/+ and Hexa-/- mice were comparable to
each other, both showing several dense lysosomes (Fig. 1, a and b). However, the efferent ducts
of Hexb-/- mice were markedly abnormal, displaying
numerous pale lysosomes in both ciliated and nonciliated cells (Fig. 1c); in some cases, a single large lysosome filled the area above or
below the nucleus of ciliated cells.
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). In
Hexa-/- mice, the number of dense lysosomes increased
dramatically to include even their basal region (Fig. 2b). In the
Hexb-/- mice, lysosomes also filled the supranuclear and
basal regions, but they were all pale-stained (Fig. 2c). In wild-type
mice, narrow cells, localized in the initial segment and intermediate
zone, were characterized by their goblet appearance and a bulging
apical cytoplasm containing the nucleus (Fig. 2a). In the
Hexa-/- and Hexb-/- mice, narrow cells lost
their goblet appearance and became enlarged and engulfed by pale
lysosomes throughout their cytoplasm (Fig. 2, b and c). Occasionally, a
single large pale lysosome was seen basally.
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) and
Hexa-/- (e.g. caput, Fig. 2e) mice showed few
dense lysosomes. In contrast, in Hexb-/- mice, principal
cells showed abundant pale lysosomes throughout their cytoplasm
(e.g. caput, Fig. 2f). The basal cells of the wild-type and
Hexa-/- mice in all epididymal regions contained
hemispherical nuclei and sparse numbers of lysosomes (Fig. 2, a, b, d,
e). Some basal cells in these epididymal regions of the
Hexb-/- mice lost their hemispherical shape and were
filled with pale lysosomes (Fig. 2, c and f). Clear cells in the caput,
corpus, and cauda epididymidis in Hexa-/- mice were
similar to those of the Hexa+/+ mice. However, clear cells
of the Hexb-/- mice were greatly enlarged and filled with
pale lysosomes (data not shown).
By electron microscopy, principal cells of the initial segment of
wild-type mice and the two types of mutant mice were characterized by a
well developed Golgi apparatus and a normal distribution and amount of
rough endoplasmic reticulum (Figs. 3, a,
b, 4a). Few small dense lysosomes were observed in the supranuclear
region of these cells in wild-type animals (Fig. 3a). However, a
dramatic increase in the number of lysosomes was apparent in the
Hexa-/- mice (Fig. 3b). These lysosomes were dense, and
some were very large in size, apparently the result of fusion with one
another. Present within them were concentric membranous profiles and
small pale vesicles (Fig. 3b). Electron microscopy confirmed that the
most marked lysosomal abnormalities in the Hexa-/- mice
were present in the initial segment and intermediate zone with only
minor alterations in the caput, corpus, and cauda regions. In the
initial segment of the Hexb-/- mice, a plethora of pale
lysosomes was observed in the supranuclear region (Fig. 4a). These pale lysosomes contained small
pale vesicles and few membranous profiles, and fusion between adjacent
lysosomes was often seen. Immunocytochemical labeling with a lysosomal
protein, SGP-1, showed gold particles over these pale structures,
identifying them as lysosomes (Fig. 4b). Electron microscopic
immunogold localization of two other lysosomal markers, cathepsin D and
Hex A (detects -subunit of Hex in Hexb-/- mice; 6), to
these pale structures further supported their identification as
lysosomes (data not shown). Electron microscopy confirmed the abundance
of pale lysosomes of variable sizes in principal cells of all other
regions of the epididymis in the Hexb-/- mice, and this
was also the case for narrow and clear cells (not shown).
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). Hexa-/-,
Hexb-/- and wild-type control mice showed quantitative
differences in ganglioside patterns in the epididymis. In the
Hexa-/- and Hexb-/- mice, a significant
increase in at least three gangliosides, G-1, G-2, and G-3 was observed
(G-2>>>G-3>>G-1, see Fig. 5). G-1 was identified as
GM2 ganglioside, based on TLC comigration with reference
GM2 ganglioside and reactivity with
GM2-specific monoclonal antibodies (KM966 and 45.66).
Control mice expressed only small amounts of GM2
ganglioside in the epididymis.
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. The spectrum indicated the presence
of several major molecular species that differed by constant mass
intervals. The masses of molecular ions at m/z = 2066.7, 2094.7,
2122.8, 2151.0, and 2179.4 form an ion series in which the masses
increase by 28 mass units. This increase is compatible with the
addition of CH2-CH2 to the fatty acid chain of
a ceramide moiety. Other observed ions that did not correspond to this
ion series such as m/z = 2044.6 and 2128, may represent
gangliosides with other modifications to the ceramide moieties. Based
on the molecular ion information, m/z = 2066.7 is in agreement
with the structure of GM1a + GalNAc or GM1b+
GalNAc. To further characterize the structure of the major gangliosides
present, the ion at m/z = 2066.7 was selected for CID. The
spectrum shown in Fig. 6b, and the data indicated in Table 2 strongly suggest that the structure at
m/z = 2066.7 molecular ion corresponded to the ganglioside of
GM1a + GalNAc. The two double cleavage fragments at
m/z = 833 and m/z = 792 are characteristic fragments of
GM1a + GalNAc. All other ions listed on Table 2 also
support this structural assignment.
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Fertility of Hex-deficient mice
Based on the severity of the epididymal abnormalities,
particularly in the Hexb-/- mice, as well as evidence in
the literature for an essential role for Hex in fertilization, we
examined breeding records of the Hex-deficient mice for alterations in
fertility. Matings between heterozygotes of either genotype,
Hexa+/- (n = 44 litters) or Hexb+/-
(n = 44 litters), produced litters of normal size (6–8
pups/litter). While Hexa-/- male mice reproduced up to at
least 1 yr, their litter sizes were significantly reduced
(Hexa+/-:6.4 ± 0.3 pups/litter where n = 44
litters; Hexa-/-:4.1 ± 0.9 pups/litter where n
= 14 litters, P 0.05, ANOVA and Duncan’s multiple
range test). Hexa-/- females produced normal sized litters
(6.0 ± 1.1, n = 5 litters). The Hexb-/- male
mice were able to sire litters of normal size (7.4 ± 0.8; n = 11
litters) between 6–9 weeks of age. These results clearly indicate that
Hex is not essential for fertilization in young adult males.
Interestingly however, despite the fact that the Hexb-/-
mice were asymptomatic until 16–20 weeks of age, matings involving six
10- to 12-week-old homozygous males did not result in litters,
suggesting that initially fertile males subsequently became
infertile.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Hex is present in the testis and epididymis and is postulated to play a
role in sperm maturation and fertilization (6, 8, 9, 11). Within the
testis, Hex has been immunolocalized to Sertoli cells, where it may
play a role in lysosomal function or facilitate germ cell release from
the seminiferous epithelium (7, 8). The potential role of Hex in
developing testicular germ cells is less clear in part due to
discrepancies between protein and mRNA expression studies. To date,
immunolocalization studies have reported low levels of Hex in germ
cells in the testis (6, 11). However, Hex -subunit mRNA was
expressed at higher levels in the testis than any other adult tissue
with developmental and germ cell isolation studies, indicating that
this expression originates in germ cells (6, 24). In contrast, Hex
ß-subunit mRNA was expressed at low levels in the testis and was
undetectable on Northern blots of pachytene spermatocyte and round
spermatid mRNA (6).
From the present study, there are several indications that Sertoli
cells and germ cells are not affected by either Hex A or Hex A and B
deficiency. Neither testis weight nor testicular sperm counts were
affected in either Hexa-/- or Hexb-/- mice,
suggesting that normal numbers of germ cells are made and that Sertoli
cells, which interact closely with germ cells to ensure normal germ
cell development and release, were functionally normal. Normal sperm
numbers, determined as counts of homogenization-resistant spermatids
and spermatozoa, indicate that germ cells in the mutant mice develop at
least to the spermatid stage. Normal fertility, at least initially,
indicates that the resulting spermatozoa are functional. At both the
light and electron microscopic levels, the Sertoli and germ cells of
the two mouse mutants were morphologically indistinguishable from
control, with no evidence of lysosomal accumulations that
characterize Hex deficiency. In particular, these data suggest
that the high testicular Hex -subunit mRNA levels that we and
others have reported (6, 24, 25) may not be important to
spermatogenesis.
In contrast to the testis, the efferent ducts and epididymis were markedly and differently affected in the Hexa-/- and Hexb-/- mice. The epididymal epithelium plays an important role in the regulation of its luminal content, through complex processes of endocytosis and exocytosis, resulting in an environment that contributes to the maturation of spermatozoa in the duct (26). The lysosome is a component of this process, as suggested by the high levels of expression of some lysosomal enzymes in this tissue (1). Hex deficiency in humans results in the classic chronic accumulation of unmetabolized substrates in lysosomes, leading eventually to an increase in the weight of the affected organ. An increase in brain weight in Tay-Sachs patients and increases in brain and visceral organ weights in Sandhoff disease patients have been reported on postmortem examination (4, 27, 28). We observed an overall increase in the weight of the epididymides of the Hexb-/- mice. Although morphological abnormalities were observed throughout the epididymis, only the weights of the caput and corpus were higher than control. Interestingly, these are the two epididymal regions with the highest Hex enzyme activity and the highest Hex ß-subunit mRNA expression (6, 11). In addition to the striking increase in size and number of lysosomes in all cell types in the epididymis of the Hexb-/- mice, an apparent fusion between adjacent lysosomes was also noted. The mechanism underlying the fusion of lysosomes in epididymal cells of the Hex-deficient mice is unclear. Lysosomal fusion has been seen in other cell types and can be induced by agents that elevate intracellular calcium levels (29).
Differences in localization and severity of the morphological abnormalities in the efferent ducts and epididymis between the two models indicate an essential function for Hex B in these tissues. This conclusion is also supported by previous studies. Beccari and colleagues (3), using the artificial Hex substrates MUG and MUGS and ion exchange chromatography to distinguish Hex A and Hex B in mouse tissues, found that that whereas the brain contained predominantly Hex A, the epididymis and kidney activities were almost entirely due to Hex B or Hex I (an intermediate-charge form of Hex, subunit composition not defined). These enzyme data correlate with mRNA expression studies that have documented the highest Hex ß-subunit mRNA levels in the epididymis and kidney, as compared with other tissues (24, 25, 30). In contrast, localized morphological defects in the initial segment/intermediate zone of the epididymis of the Hexa-/- mice support a functional role for Hex A that cannot be replaced by Hex B, at least in these regions of the duct.
We and others have previously shown that both the Hexa-/- and Hexb-/- mice accumulate GM2 ganglioside in the brain (12, 13). Our data here suggest that the lysosomal accumulations in the cells of the efferent ducts and epididymis of the Hex-deficient mice are also gangliosides. However, unlike accumulations in the brain, only small amounts of GM2 ganglioside were found in the epididymis, whereas significant quantities of two non-GM2 gangliosides, G-2 and G-3, were identified in the Hexa-/- and Hexb-/- mice. These two non-GM2 gangliosides may be specific to the epididymis as they do not accumulate in the liver, another peripheral tissue, in the Hexb-/- mice (12). Presence of two minor non-GM2 gangliosides with terminal N-acetylgalactosamine (GalNAc-GM1b and GalNAc-GD1a) in human Tay Sachs brain has previously been reported (31). Because the testis is unaffected in the mutant mice, we suggest that substrates for Hex, either secreted by Sertoli cells or present as a component of sperm, that are normally endocytosed by epididymal epithelial cells and processed in lysosomes, accumulate in the enlarged lysosomes of the Hex-deficient mice.
Our fertility data provide new insight into the role of Hex in male reproductive function. In a previous report, Hex was localized to the acrosome of mouse sperm by biochemical and immunofluorescence studies and a competitive inhibitor of Hex, PUGNAC [O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino N-phenylcarbamate], inhibited sperm penetration through the zona pellucida (9). Based on these results, the authors suggested that sperm require Hex at the time of fertilization to penetrate the egg zona. The fact that the Hexb-/- mice produced litters of normal size between 6–9 weeks of age would argue that Hex is not essential for fertilization. Interestingly, some alterations in fertility were noted; litters sired by Hexa-/- males were small, and no litters were produced from breeding studies with a small number of 10- to 12-week-old Hexb-/- males. Although the Hexb-/- male mice appeared healthy and normally active between 9–12 weeks of age, it is possible that behavioral abnormalities and muscle weakness could explain their infertility. Alternatively, the alterations in fertility could be secondary to epididymal abnormalities. As for the brain in Tay Sachs and Sandhoff diseases, the epididymis may become progressively more dysfunctional with time as lysosomal accumulations increase. Prospective detailed fertility studies are needed to determine the basis of the alterations in fertility in the Hex-deficient mice. Because the Hex A- and B-deficient mice were initially fertile, we propose that the subsequent decrease in fertility is secondary to epididymal dysfunction and abnormalities in the luminal environment that supports sperm maturation.
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Acknowledgments |
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Footnotes |
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2 Scholar of the Fonds de la recherche en santé du
Québec.
Received November 24, 1997.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and
ß-subunit gene expression in the rat testis and epididymis. Mol
Reprod Dev 46:227–242[CrossRef][Medline]
subunit
of hexosaminidase A. Genomics 24:110–119[CrossRef][Medline]
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