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The Burnham Institute (N.S., D.N., S.K., K.S., M.N.F.), La Jolla, California 92037; and Departments of Pediatrics and Molecular and Integrative Physiology (B.C.P.), University of Kansas Medical Center, Kansas City, Kansas 66160
Address all correspondence and requests for reprints to: Dr. Michiko N. Fukuda, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, California 92037. E-mail: michiko{at}burnham-inst.org
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Abstract |
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Introduction |
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To define the interactions between the blastocyst and endometrial epithelial cells in humans, we previously characterized interactions between two human cell lines, trophoblastic teratocarcinoma and endometrial adenocarcinoma. Subsequently, we identified novel proteins designated trophinin, tastin and bystin, which mediate apical cell adhesion between these two cell types (13, 14, 15, 16). Trophinin is an intrinsic membrane protein mediating homophilic cell adhesion. Tastin and bystin are cytoplasmic proteins required for trophinin to exhibit adhesion activity, most likely by organizing multivalent adhesive foci on the cell surface.
In humans, the endometrium is under strict hormonal control and is generally not permissive to implantation (17, 18). During a relatively short period of time in hormonally regulated cycles, the surface epithelium of the endometrium becomes receptive to trophoblast attachment. In humans, trophinin is not expressed during proliferative and ovulation phases, whereas strong expression of trophinin is detected in a restricted region of human endometrium at early secretory phase or the time of the implantation window (13, 15, 19). In the late secretory phase, trophinin is found in mucus as well as in the glandular epithelium. In monkey blastocysts, trophinin is strongly expressed at the embryonic pole of the trophectoderm. Trophinin is also expressed in the trophoblast and endometrial epithelial cells at the implantation site in the monkey. In human placenta from the early first trimester, trophinin is found in chorionic villi and the endometrial glandular epithelium at the utero-placental interface, which presumably corresponds to the implantation site (19). In placenta from the sixth week pregnancy, trophinin proteins are found on the apical surface of syncytiotrophoblast in the chorionic villi. Trophinin is internalized to lysosomal membranes and disappears from the placenta after the 10th week pregnancy. These expression patterns of trophinin in human placenta suggest that trophinin plays an important role in blastocyst implantation and early placental development in humans.
In the mouse, coordinated effects of progesterone and estrogen primarily regulate the establishment of a receptive uterus (20, 21). Upon mating, increasing levels of progesterone from the newly formed corpora lutea directs stromal cell proliferation, which is potentiated by estrogen secreted from the ovary 3 days after mating. The luminal epithelium becomes differentiated for interactions with the blastocyst, which occurs at 4.0 days post coitus (dpc). The initial step of mouse blastocyst implantation is an apposition in which a hatched blastocyst pauses in the endometrial lumen. Endometrial epithelial surfaces have well-developed microvilli (22) with negatively charged mucin (23). The uterine lumen is obliterated at the implantation site as a result of fluid uptake by the uterine epithelium and edematous swelling of the uterine stroma (23, 24). At this stage, the blastocyst does not adhere to the uterine epithelium, but respective microvilli are modified to a flat apposition between the two apical epithelial plasma membranes (22). During this time, endometrial epithelium and blastocysts interact to each other, and an activity of the blastocyst makes the uterine epithelium more receptive for implantation (3, 6, 8).
Among factors likely be involved in mouse embryo implantation, amphiregulin (AR) (24) and heparin-binding EGF-like growth factor (HB-EGF) (25, 26, 27) are up-regulated in the endometrium in response to blastocyst implantation. At the onset of attachment, levels of AR messenger RNA (mRNA) are high in the luminal epithelium surrounding the blastocyst (3, 24), suggesting an embryonic influence on AR expression. HB-EGF is expressed exclusively in the mouse luminal epithelium surrounding the blastocyst (3, 25). Conversely, Muc-1, a heavily glycosylate mucin modulating the interaction between blastocysts and endometrial epithelial cells, is down regulated at the site of blastocyst implantation (15, 28).
Here we report the expression of trophinin in the mouse uterus. Our results indicate that trophinin is transiently expressed in the mouse uterus at the time of embryo implantation. However, compared with AR and HB-EGF, the spatial expression pattern of trophinin is not restricted to the implantation site. Our data indicate that trophinin expression by the mouse uterus is regulated by ovarian hormones but not by implanting blastocyst.
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Materials and Methods |
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-methyl-17-hydroxy-progesterone acetate) and estrogen
(E2, ß-estradiol) were purchased
fromSigma (St. Louis, MO).
Nucleotide sequences of mouse trophinin
The amino acid sequence of the coding region of mouse trophinin
was deduced from the sequence of a genomic clone encoding mouse
trophinin (Nadano and Fukuda, unpublished data). The sequence is
available from GenBank under accession number AF145589.
Antitrophinin antibody
Polyclonal antibody was raised against a synthetic peptide,
TSTDFSGGLNHNADFN. The peptide represents amino acid residues 918 to 933
of mouse trophinin. This peptide was conjugated to keyhole limpet
hemocyanin and used to immunize a rabbit. The rabbit IgG was purified
from the antisera using protein A-Sepharose column and used as purified
antibody.
Animals and tissue preparation
CD-1 mice (Charles River Laboratories, Inc.
Raleigh, NC) were housed in the animal care facility at the Burnham
Institute according to NIH and institutional guidelines on the care and
use of laboratory animals. Adult female mice (5–6 weeks old) were
mated with fertile males of the same strain. The morning of the vaginal
plug is designated as 0.5 dpc. Mice were killed between 0.5 dpc and 6.5
dpc, and whole uteri were collected. Pseudopregnant mice were produced
by mating with vasectomized males. To determine whether embryos
influence uterine expression of trophinin, blastocysts collected at 3.5
dpc were transferred to the uteri of 2.5 dpc pseudopregnant females.
Each horn of the uterus received 8 blastocysts. Uterine transferred
pseudopregnant females were killed at various times to isolate uteri.
Ovariectomized CD-1 females rested for 2 weeks were purchased from
Charles River Laboratories, Inc. Ovariectomized mice were
injected with estrogen (E2, 25 ng/mouse) or with
progesterone (P4, 1 mg/mouse). All steroids were
dissolved in sesame oil and injected sc (0.1 ml/mouse) (8, 29). The control mice received sesame oil only. Mice were killed
at various times after the hormone injections, and their uteri were
collected. To induce and maintain delayed implantation, mice were
ovariectomized in the morning (0800–0900 h) of 3.5 dpc and received
daily injections of P4 (2 mg/mouse) from 4.5 and
6.5 dpc (8, 29). To terminate delayed implantation and
induce blastocyst activation, the P4 primed,
delayed implanting mice were given an injection of
E2 (25 ng/mouse) on the third day of the delay
(6.5 dpc). Mice were killed at 12 and 24 h after
E2 injection. Under these conditions, the first
visibly detectable implantation sites after blue dye injection became
evident 18–24 h after an E2 injection
(21). Uterine tissues were flash frozen in liquid freon
and stored at -70 C until use.
Western blot analysis
Freshly isolated tissues, 100 mg each from uteri, brain, and
spleen, were homogenized in 0.5 ml of 1x SDS (sodium dodecyl sulfate)
sample buffer (30) containing protease inhibitor cocktails
(Sigma) at 4 C. The homogenates were boiled for 5 min, and
insoluble materials were removed by centrifugation. Proteins in the
supernatant (10 µl/lane) were resolved by electrophoresis in a 7.5%
SDS-polyacrylamide gel. Proteins were transferred to a nitrocellulose
filter in 25 mM Tris and 0.19 M glycine. The
filter was blocked in TBST (0.2 M Tris-HCl buffer, pH 7.4,
containing 0.15 M NaCl and 0.1% Tween 20) containing 2%
BSA and 1% normal goat serum for 1 h at room temperature. The
filter was then incubated with 1:2000 diluted (final concentration 2
µg/ml) purified antitrophinin antibody in the blocking solution for
1 h at room temperature. After washing with TBST, the filter was
incubated with diluted (1:1000) biotinylated goat antimouse IgG
antibody (ABC kit, Vector Laboratories, Inc. Burlingame,
CA) for 30 min. After washing with TBST, the filter was incubated with
diluted (1:2000) peroxidase conjugated avidin (ABC kit) for 10 min,
washed with TBST, and immunoreactive bands were visualized using
diamino benzidine peroxidase substrate solution (Vector Laboratories, Inc.).
Northern blot analysis and RT-PCR
Poly(A)+ RNA was isolated from various
organs and uteri from pregnant CD-1 female mice using
an Oligotex RNA isolation kit (QIAGEN, Valencia, CA).
Northern analysis was performed as described (31) using a
[32P]-labeled DNA probe, which corresponds to
nucleotide residues 3,141 to 3,367 (starting at the ATG initiation
codon) or 3' region of the coding sequence of mouse trophinin DNA.
RT-PCR was performed using ThermoScript RT-PCR system (Life Technologies, Inc.). Each 5 ng Poly(A)+
RNA was subjected to complementary DNA (cDNA) synthesis, and a portion
of cDNA was subjected to PCR reaction using mouse trophinin gene
specific primers; 5'-GACCGCCAAGCACCGGTACT-3' (forward) and
5'-AGTATTGTTGCAGTTAGCGTT-3' (reverse). This primer set will amplify 128
bp in 3' region of the trophinin cDNA. The same primer set amplifies
genomic DNA of mouse trophinin gene and gives 281 bp amplicon as this
region contains a 153 bp intron. PCR reaction was performed after
heating at 94 C for 5 min, 25 cycles of 94 C for 30 sec, 72 C for 30
sec, and 72 C for 30 sec. Actin cDNA was amplified using primers
provided by the RT-PCR kit as a control primer set.
Immunohistochemistry
Mouse uteri were fixed in 4% paraformaldehyde in PBS at 4 C for
20 h and embedded in paraffin. Tissue sections, each 4 µm, were
made by microtome. Immunostaining was performed using the polyclonal
antimouse trophinin antibody described above. The antibody was purified
on a protein A affinity column and used at 1:200 (protein 20 µg/ml)
dilution. Biotinylated goat antirabbit IgG antibody and peroxidase
conjugated avidin (ABC kit, Vector Laboratories, Inc.
Burlingame, CA) were used. Counterstaining was performed using
hematoxylin. Frozen uteri were sectioned (12 µm) and mounted onto
poly-L-lysine-coated glass slides, fixed in 4%
paraformaldehyde in PBS for 10 min and washed in PBS. Immunostaining
was performed by incubating the sections with purified polyclonal
antimouse trophinin antibody diluted to 1:2000 (protein 2 µg/ml) for
15 h at 4 C. A Zymed Laboratories, Inc.-Histostain-SP
kit for rabbit primary antibodies and AEC single solution of peroxidase
substrate (Zymed Laboratories, Inc., San Francisco, CA)
were used for detecting the site of immunoreactive proteins, which were
seen as red deposits. Sections were lightly counterstained with
hematoxylin.
In situ hybridization
Mouse uteri were isolated and immediately fixed in 4%
paraformaldehyde dissolved in PBS at 4 C for 20 h. Fixed tissues
were embedded in paraffin. Sections, each 10 µm, were made for
in situ hybridization under RNase free conditions. RNA
probes for mouse trophinin were prepared as follows. A portion of the
coding region of mouse trophinin (nucleotides 3,141 to 3,367 starting
at the ATG initiation codon) was amplified by the PCR using a primer
pair 5'-CCGAATTCAGGACCTGGCTTCGGTGGAC-3' (EcoRI
site underlined) and
5'-TTAAGCTTCCACCAAAGCCAGTGCTGGT-3' (HindIII site
underlined). The resulting fragment was subcloned into
pGEM-3Zf (+) (Promega Corp., Madison, WI) at the
EcoRI and HindIII sites, and the resultant vector
was used as a template for preparing antisense and sense RNA probes. A
digoxigenin (DIG)-labeled antisense RNA probe was obtained using
EcoRI-cut template and SP6 RNA polymerase with a DIG RNA
labeling kit (Roche Molecular Biochemicals, Indianapolis,
IN). Similarly, a control sense probe was prepared using
HindIII-cut template and T7 RNA polymerase. In
situ hybridization was performed as described previously
(19, 32). After tissue sections were deparaffinized in
Hemo-De (Fisher Scientific, Pittsburgh, PA), hydrated
slides were immersed in 0.2 M HCl for 20 min and
digested with 100 µg/ml proteinase K at 37 C for 20 min, followed by
post fixation in 4% paraformaldehyde in PBS, pH 7.4. The slides were
rinsed with 2 mg/ml glycine, and acetylated for 10 min in freshly
prepared 0.25% acetic anhydride in 0.1 M
triethanolamine (pH 8.0). After prehybridization in 50% deionized
formamide/2x SSC for 1 h at 45 C, the slides were hybridized with
0.5 µg/ml of the antisense or sense probe in 50% deionized
formamide, 2.5 mM EDTA (pH 8.0), 300
mM NaCl, 1x Denhardt’s solution, 10% dextran
sulfate, and 1 mg/ml brewers yeast transfer RNA at 45 C for 16 h.
After hybridization, the slides were washed in 50% formamide/2x SSC
for 1 h at 45 C and digested with 10 µg/ml RNase A at 37 C for
30 min. The slides were treated with 1x SSC/50% formamide at room
temperature for 30 min and then subjected to immunohistochemistry for
detection of hybridized probes using an alkaline phosphatase-conjugated
anti-digoxigenin antibody (Roche Molecular Biochemicals).
The alkaline phosphatase reaction was visualized with
5-bromo-4-chloro-3-indolyl phosphate and nitroblue tetrazolium. Tissue
sections were mounted in glycergel (DAKO Corp.,
Carpinteria, CA) and examined by light microscopy.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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).
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). This size
matches to the expected size, 107 kDa, for mouse trophinin protein. The
positive signal in the brain but not in the spleen is consistent with
the result of Northern blot (Fig. 1A
).
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Expression of trophinin in mouse uterus
Northern analysis of pregnant mouse uteri (Fig. 1B) showed that
trophinin transcripts are expressed on the day of mating or 0.5 dpc,
and reappears on 3.5 dpc. Mouse blastocysts implant at 4.0 dpc.
Therefore, expression of trophinin between 3.5 and 5.5 dpc coincides
with the timing of embryo implantation. Trophinin mRNA disappears from
the uterus after implantation, or after 6.5 dpc.
Western blot analysis from the uterine tissue lysates showed a 110-kDa
band from 4.5 dpc, while this band was not detected in the uterus from
2.5 dpc (Fig. 2). These results indicate that both trophinin transcript
and protein are expressed in the mouse uterus at the time of
implantation.
A positive trophinin mRNA signal on 0.5 dpc (Fig. 1B) suggests that
trophinin is expressed in mouse uterus before mating. In
situ hybridization analysis of nonpregnant mouse uterus detected
weak expression of trophinin mRNA in the uterus at the proestrus stage
(Fig. 3A). Strong expression of trophinin
mRNA was seen in luminal epithelial cells at the estrus stage (Fig. 3B). No signals were detected in the uterus at diestrus stage (Fig. 3C). This evidence suggests that trophinin expression in mouse uterus
is controlled by steroid hormones secreted by the ovary.
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). Trophinin protein was found in
the apical plasma membranes of luminal epithelium as well as in mucus.
The mucus form trophinin was only found at the estrus. This pattern
suggests a possibility that trophinin protein is synthesized in the
luminal epithelial cells and is shed to the endometrial lumen. Similar
observations have been made on human trophinin: in the late secretory
phase of the human endometrium, trophinin is found in the mucus
(13).
Effect of ovarian hormones on trophinin expression in mouse
uterus
To elucidate whether trophinin expression is regulated directly by
ovarian hormones, ovariectomized mice were analyzed for expression of
trophinin. In situ hybridization revealed that trophinin is
not expressed in the uteri of ovariectomized mice (Fig. 4A). When ovariectomized mice were
administered with E2, trophinin was strongly
expressed in both epithelial cells and stromal cells (Fig. 4B). On the
other hand, P4 had no obvious effect on trophinin
expression (Fig. 4C).
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) and RT-PCR analyses (Fig. 5). Following administration of
E2, trophinin transcripts started to be expressed
within 2 h, peaked at 8 h, and continued to be expressed for
24 h (Fig. 4, E and F, and Fig. 5). Under these conditions,
trophinin transcripts were equally expressed in uterine luminal
epithelial cells and glandular epithelial cells, and weakly in stromal
cells.
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). Trophinin transcripts and proteins
were detected in the uteri at 4.5 dpc from normal pregnancies (Fig. 6, A and D) and from pseudopregnancies (B, E). A pseudopregnant uterus
that received blastocysts (C, F) appeared no different from a uterus
that did not receive blastocysts (B, E). These results suggest that
blastocysts do not have significant effect on trophinin expression in
the mouse uterus.
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, a and b). The dormant blastocysts were
not stained with the antibody.
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, c and d) and 24 h (e, f) after E2
treatment showed that epithelial cells surrounded the blastocyst became
weaker than those luminal epithelium adjacent to the blastocysts. At
these stages, glandular epithelia are stained strongly. An activated
and implanting blastocyst was not stained with the antibody. These
results support the finding that implanting blastocysts have no
significant influence on trophinin expression by mouse uterine
epithelial cells. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present study shows that trophinin expression in the pregnant mouse
uterus peaks between 3.5 and 5.5 dpc (Fig. 1B). This period coincides
with the timing of blastocyst implantation (33). However,
trophinin transcripts and proteins were detected in the entire uterine
epithelium in both luminal and glandular epithelial cells (Fig. 6, A
and D). When trophinin were overexpressed by E2
injection, transcripts were clearly detected in stromal cells (Fig. 4, B, E, and F). Furthermore, no differences were seen in the levels of
trophinin transcripts and proteins in uteri from normal (Fig. 6, A and
D) and pseudopregnancies (B, E), and no differences were found in
pseudopregnant mouse uteri in the presence (Fig. 6, C and E) or absence
(B, E) of blastocysts. These results suggest that the mouse blastocysts
do not affect trophinin expression by the uterus. These results are
consistent with observations of delayed implantation, in which
preferential localization of trophinin proteins to the luminal
epithelium surrounding the blastocysts does not occur (Fig. 7). Our
results exclude the possibility that an embryonic factor is involved in
trophinin expression in the mouse uterus and are consistent with the
finding that an administration of E2 to an
ovariectomized mouse induced trophinin expression in the mouse uterus
(Figs. 4B and 5).
Our findings show that P4 does not promote
trophinin expression (Fig. 4, C and D). Either a single (C) or multiple
(D) administration of P4 did not induce trophinin
expression in ovariectomized mice. However, the effects of
P4 may differ depending on the context. In the
delayed implantation model, mice injected with P4
for 3 days exhibited high levels of trophinin proteins in the uterus
(Fig. 7, a and b). These mice were ovariectomized on day 4 of
pregnancy, and P4 injection was started from day
5. Thus, these mice were not devoid of circulating
P4. In contrast, ovariectomized mice were rested
for 2 weeks to eliminate P4 completely from the
circulation. Thus, in the delayed implantation model,
P4 injections may not lead a production of
trophinin but may maintain the day 4 trophinin level during the delayed
period.
Here we show that implanting mouse blastocysts express no trophinin
protein (Fig. 7). This contrasts with observations of primate
blastocysts showing high levels of trophinin proteins on the
trophectoderm surface (6). Although there are no direct
data available as to whether human blastocysts express trophinin, our
previous analyses on human placenta tissues from early pregnancy
demonstrated high levels of trophinin proteins at the apical plasma
membranes and lysosomal membranes of the syncytiotrophoblast
(19). Therefore, it is likely that a human blastocyst
expresses high levels of trophinin protein at the time of implantation.
The levels of trophinin protein on the trophectoderm surface during
implantation may differ significantly in different mammalian
species.
A number of studies show that the processes of embryo implantation vary in different species (1, 34, 35, 36, 37, 38). In mouse, a blastocyst attaches to the uterine epithelium with its mural pole trophectoderm (36, 37, 38). The trophoblast comes into flat apposition with the uterine epithelium, which then dies by apoptosis and is phagocytosed by the cellular trophoblast. The trophoblast then differentiates into primary giant cells and penetrates the maternal tissues. In contrast, the human blastocyst attaches to the endometrium through the syncytial trophoblast at the embryonic pole (38, 39). The adjacent endometrial epithelial cells surround the blastocyst, giving an appearance of the blastocyst passing through the uterine epithelium. Considering these significant differences during the initial and subsequent steps of implantation, it is possible that trophinin functions as a cell adhesion molecule only in humans. Nevertheless, trophinin is expressed in the mouse uterus at the time coincides with implantation, suggesting some role in the mouse uterus. In this regard, it will be important to determine the expression patterns of trophinin in various mammalian species.
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Acknowledgments |
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Footnotes |
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2 Present address: Department of Gynecology and Obstetrics, Keio
University School of Medicine, Shinanomachi, Tokyo 160,
Japan.
3 Present address: Molecular Oncology Laboratory, Tsukuba Life
Science Center, RIKEN, Tsukuba, Ibaraki 305-0074, Japan.
4 Present address: Department of Medicine, Brigham and Women’s
Hospital, Harvard Medical School, Boston, Massachusetts
02115.
Received March 23, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-interferon
pregnancy recognition signal in ruminants. Exp Biol Med 37:215–229
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