ARTICLE |
Correspondence to: Hiroki Sawa, Dept. of Neurosurgery, Kyorin Univ., School of Medicine, Mitaka, Tokyo 181, Japan.
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Summary |
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We investigated the expression of the immunoglobulin superfamily cell adhesion molecule, C-CAM, in developing and mature rat placenta. By immunohistochemical staining at the light microscopic level, no C-CAM-expression was seen before Day 9 of gestation, when it appeared in the trophoblasts of ectoplacental cones. On Day 10.5, spongiotrophoblasts and invasive trophoblasts around the maternal vessels of the decidua basalis were stained positively. On Day 12.5, C-CAM was detected in the spongiotrophoblasts of the junctional layer, but labyrinth trophoblasts and secondary giant trophoblasts were not stained. On Day 17.5, C-CAM was found only in the labyrinth and lacunae of the junctional layer. At this stage, both the labyrinth cytotrophoblasts of the maternal blood vessels and the endothelial cells of the embryonic capillaries were strongly stained. Placental tissues from gestational Days 12.5 and 17.5 were analyzed by immunoelectron microscopy to determine the location of C-CAM at the subcellular level. On Day 12.5, positive staining of the spongiotrophoblasts was observed, mainly on surface membranes and microvilli between loosely associated cells. On Day 17.5, staining was found primarily on the microvilli of the maternal luminal surfaces of the labyrinth cytotrophoblasts, and both on the luminal surface and in the cytoplasm of endothelial cells of the embryonic vessels. RT-PCR analysis and Southern blotting of the PCR products revealed expression of mRNA species for both of the major isoforms, C-CAM1 and C-CAM2. Immunoblotting analysis of C-CAM isolated from 12.5-day and 14.5-day placentae showed that it appeared as a broad band with an apparent molecular mass of 110-170 kD. In summary, C-CAM was strongly expressed in a specific spatiotemporal pattern in trophoblasts actively involved in formation of the placental tissue, suggesting an important role in placental development. In the mature placenta, C-CAM expression was confined to the trophoblastic and endothelial cells lining the maternal and embryonic vessels, respectively, suggesting important functions in placental physiology. (J Histochem Cytochem 45:1021-1034, 1997)
Key Words: C-CAM, rat placenta, immunohistochemistry, RT-PCR, immunoelectron microscopy
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Introduction |
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In many mammals, implantation involves invasion of the endometrium by trophoblasts to establish the placenta and set up communication with the maternal blood circulation (
C-CAM is a well-characterized cell adhesion molecule of the IgS family (
C-CAM is a transmembrane, highly glycosylated protein that occurs in several isoforms owing to differential splicing (
It has recently been found that C-CAM1 isoforms in both rat and mouse appear to be negative regulators of cellular growth and function as tumor suppressors in both prostate and colon carcinogenesis (
In addition to cell adhesion and transmembrane signaling it appears that C-CAM can influence membrane transport. Therefore, C-CAM1 has been found to affect transport of bile acids through the plasma membrane (
To learn more about the functions of C-CAM, we decided to determine when and where it appears during postimplantation embryonic development. We now report that C-CAM becomes expressed in proliferating and invading trophoblasts in the developing placenta from Day 9 of gestation. In the mature placenta it is expressed in cytotrophoblasts of the maternal blood lacunae and in embryonic capillary endothelial cells.
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Materials and Methods |
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Animals
Sprague-Dawley rats were obtained from the local breeding colony at the animal facility of Kyorin University, School of Medicine. The day on which a vaginal plug became apparent was regarded as Day 0.5 of gestation (E0.5). Rat placentae of gestational days 6.5 (E6.5), 7.5 (E7.5), 8.5 (E8.5), 10.5 (E10.5), 12.5 (E12.5), 14.5 (E14.5), 15.5 (E15.5), 17.5 (E17.5), and 19.5 (E19.5) were studied. The animals were sacrificed by ether anesthesia and the placentae were removed and fixed with 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4 (PB) for light and electron microscopic immunohistochemical analysis. For immunoblotting and RNA analyses, the tissues were immediately frozen in liquid nitrogen and stored at -80C until used.
Antibodies
Rabbit polyclonal antibodies against purified rat liver C-CAM were produced and characterized as previously described (Odin et al. 1987). They were shown to be monospecific for C-CAM by immunoblotting of liver. Rabbit antibodies against human pregnancy-specific glycoproteins (PSG) were obtained from Dako (Glostrup, Denmark). They have been demonstrated to crossreact with PSGs of rat origin (
Light Microscopic Immunohistochemistry
Rat placental tissues were fixed with 4% paraformaldehyde in 0.1 M PB and embedded in paraffin. Sections (5 µm) were cut, deparaffinized, and blocked with 0.3% H2O2 in methanol to quench endogenous peroxidase activity. Immuno-staining was performed using the avidin-biotin-peroxidase complex (ABC) method (
Electron Microscopic Immunohistochemistry
The tissues were fixed with 4% paraformaldehyde in PB, immersed in a graded series of sucrose in 0.1 M PB up to 30% sucrose, embedded in OCT compound (Tissue Tek; Miles, Elkhart, IN), and frozen in liquid nitrogen. Sections (20 µm thick) were cut on a Histostat microtome (Meiwa; Tokyo, Japan) and mounted on plastic plates. The plates were immunostained as described for light microscopic immunohistochemistry. They were then washed with PB, dehydrated in a graded series of ethanols, immersed in propylene oxide, and embedded in epoxy resin. Sections (1 µm thick) were cut and stained with toluidine blue for light microscopic examination. Selected areas were then thin-sectioned, stained with uranyl acetate and lead nitrate, and examined with a Hitachi H-7000 electron microscope at 75 kV.
Immunoblotting
Rat placentae were stored at -80C until used. To examine whether placental C-CAM is an integral membrane protein, the samples were analyzed by phase separation in Triton X-114. Placental tissues were homogenized in 2% Triton X-114 (Sigma; St Louis, MO), 1 mM phenylmethylsulfonyl fluoride (Sigma) in TBS, in a glass homogenizer. The homogenate was placed on ice for 10 min and then centrifuged at 3000 x g for 5 min. The supernatant was layered on a 0.5-ml sucrose cushion (6% sucrose, 0.06% Triton X-114 in TBS) and the tubes were incubated for 10 min at 30C. The samples were then centrifuged at 18,000 x g for 5 min at RT, which resulted in separation into a clear upper aqueous phase and an oily lower detergent phase. Each of the two phases was subjected to a second phase separation by centrifugation as described by
RT-PCR and Southern Blot Hybridization
Total RNA was prepared from rat placentae using Isogen solution according to the manufacturer's protocol (Wako). In brief, placental tissues were disrupted in Isogen solution and an equal volume of chloroform was added. After centrifugation for 5 min at 18,000 x g, the aqueous phase was precipitated with isopropanol. PolyA(+) RNA was purified using oligo-dT-latex (Oligo-dT 30 super; Takara, Japan) beads. Using 1 mg of polyA(+) RNA as template, cDNA was then produced with reverse transcriptase (Promega; Madison, WI) and random priming. The resultant cDNA was amplified by PCR with 40 cycles at 95C for 45 sec, 55C for 45 sec, and 72C for 45 sec, following the manufacturer's protocols of the GeneAmp RNA system (Perkin Elmer; Norwalk, CT). The primer sets used for amplification of C-CAM consisted of two forward primers: F5,Xho-1 (5'-GCC TCG AGA TGG AGC TAG CCT CGG CTC GT- 3'; nt. 1-21) and F3 (5'-GCA AGC TTT TTT GAG CCA GTG ACT CAG CCC TCC-3'; nt. 955-978), and a reverse primer B-6,Xho-1 (5'-GCC TCG AGC AGG ACA GAC AAT GTC AC-3'; nt. 1557-1574). The indicated nucleotide (nt) numbers refer to the C-CAM cDNA nucleotide sequence (
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Results |
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Spatiotemporal Expression of C-CAM in Placenta
The temporal expression pattern of C-CAM in the developing placenta was investigated by immunohistochemistry at the light microscopic level. No C-CAM was detected in the embryonic or extraembryonic cells on gestational Days 6.5 or 7.5. On day E8.5 it appeared in the trophoblasts of the ectoplacental cone (Figure 1A), and on Day E10.5 both spongiotrophoblasts (Figure 1C) and trophoblasts invading the maternal blood vessels (Figure 1D and Figure 2A) of the decidua basalis were positively stained. The spongiotrophoblasts of the junctional zone continued to express C-CAM on Day E12.5 (Figure 1E and Figure 2B) at a high level, but at this stage no staining was seen in the labyrinth or in secondary trophoblasts (Figure 1E). Labyrinth trophoblasts, and maternal blood lacunae of the junctional layer became stained by anti-C-CAM antibodies on Day E15.5 (Figure 1G), whereas most of the trophoblasts of the junctional layer no longer expressed C-CAM at this stage (Figure 1G). On Day E17.5, C-CAM expression was observed only in the labyrinth and in the lacunae of the junctional layer (Figure 1H). At higher magnification it could be seen that both the maternal surfaces of the labyrinth cytotrophoblasts and the endothelial cells of the embryonic capillaries were stained at this stage (Figure 2C). Only the cytotrophoblasts, and not the syncytiotrophoblasts, of the labyrinthine wall were stained. By Day E19.5 the expression pattern of C-CAM was the same as on Day E17.5. No staining was observed with nonimmune rabbit serum (Figure 1B and Figure 1F).
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In addition to the trophoblast and embryonic endothelial cell lineages, C-CAM was also expressed in maternal cells in the uterine cavity epithelium and in the metrial gland on Day E10.5 (Figure 1C), and in the endothelial cells of the endodermal sinus yolk sac on Day 17.5 (Figure 1H).
It is well known that pregnancy-specific glycoproteins (PSGs) which, like C-CAM, belong to the CEA gene family, are expressed at high levels in placentae of both humans and rodents (
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Subcellular Localization of C-CAM
Light microscopic immunohistochemistry demonstrated that C-CAM was localized to the cell surfaces of the trophoblasts at all stages of placental development (Figure 1 and Figure 2). To determine the localization of C-CAM at higher resolution, we made immunoelectron microscopic analyses of placental tissues from gestational Days E12.5 and E17.5. At Day E12.5 C-CAM was located on the surface membranes of spongiotrophoblasts of the junctional layer (Figure 4A) and of trophoblasts invading maternal blood vessels (Figure 4B and Figure 4C). Areas of close cell-cell contact were not significantly stained, but C-CAM was strongly expressed in areas of loose cell-cell association and on free cell surfaces. In the areas of loose cell-cell association, primarily microvillar structures were C-CAM-positive (Figure 4A and Figure 4B). Invasive trophoblasts were also stained on microvilli facing the maternal blood vessels (Figure 4C).
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At Day E17.5 the distribution of C-CAM was different from that on Day E12.5 at the light microscopic level (Figure 2C). At Day E17.5 it was primarily the luminal surfaces of the trophoblasts of the blood lacunae and the embryonic endothelial cells that showed strong C-CAM staining. At the electron microscopic level it was seen that the microvilli of the labyrinth trophoblasts, which protruded into the maternal blood circulation, were stained. The embryonic endo-thelial cells expressed C-CAM both on the luminal surfaces and intracellularly, presumably in intracellular membranes (Figure 4D and Figure 4E).
Molecular Analyses of C-CAM
The expression of C-CAM was investigated at the protein level by immunoblotting. At Days E12.5 and E14.5 C-CAM appeared as a broad band with an apparent molecular mass of 110-170 kD. The broad band probably reflected a high but heterogeneous degree of glycosylation. All detectable C-CAM could be extracted by Triton X-114, and none was left in the insoluble tissue residue. All of the extracted C-CAM partitioned into the detergent phase of Triton X-114 (Figure 5), demonstrating that rat placental C-CAM behaves as an integral membrane protein.
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No discrete bands were seen in the broad C-CAM band, and therefore this analysis did not reveal whether different C-CAM isoforms were expressed. Because no isoform-specific antibodies that could be used for this purpose were available, we investigated C-CAM expression at the mRNA level. This was done in Days E12.5, E14.5 and E17.5 placentae using the RT-PCR technique. The primer set of F5,Xho-1/B6,Xho-1-amplified fragments of approximately 1500 BP (Figure 6A) at all the developmental stages, whereas the primer combination F3/B6,Xho-1 amplified a poorly resolved doublet containing two bands of 638 and 585 BP (Figure 6A), respectively. This suggested that transcripts for both C-CAM1 and C-CAM2 occurred.
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It was not possible to determine if the 1500-BP band, amplified by the primer set F5,Xho-1/B6,Xho-1, contained more than one band. Therefore, this product was reamplified using the primer set combination F3/B6,Xho-1. This resulted in two fragments of 638 and 585 BP (Figure 6B), which were seen in rat placentae of all developmental stages. Southern blot analysis of these cDNAs demonstrated that probe F hybridized with the 638-BP fragment, and probe G hybridized with both the 638 BP and the 585 BP fragment (Figure 6D, Lanes 1 and 3). Nonlabeled oligonucleotides abolished the hybridization of the labeled probes F and G (Figure 6D, Lanes 2 and 4). These results showed that the 638-BP fragment represented C-CAM1 and the 585-BP fragment represented C-CAM2.
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Discussion |
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Employing specific antibodies in light and electron microscopic analyses, we found that the cell adhesion molecule C-CAM is expressed in rat placenta in a characteristic spatiotemporal pattern in two cell lineages of embryonic origin, trophoblasts and capillary endothelial cells. C-CAM is a member of the CEA gene family, which comprises several structurally related proteins (
Previous investigations by one of us showed that C-CAM is expressed early in the preimplantation embryo by the trophectoderm of the blastocyst (
At Day E15.5 the rat placenta has acquired its mature histological structure as a result of cell proliferation, cell differentiation, and reorganization of the tissue architecture. Two significant features of the expression pattern of C-CAM of relevance for placental development and function could be distinguished. First, C-CAM was expressed in cells that are highly active and instrumental in forming the placental histostructure, i.e., the trophoblasts of the ectoplacental cone, the spongiotrophoblasts of the junctional zone, and the trophoblasts invading the maternal blood vessels. However, C-CAM was not expressed in the trophoblasts of the labyrinth before the mature placental structure was reached. When C-CAM appeared in the labyrinthal trophoblasts it was no longer seen in the trophoblasts of the junctional layer. This expression pattern suggests that C-CAM has important roles in the development of the tissue structure of the placenta. Second, in the mature placenta C-CAM was expressed both in the trophoblasts lining the maternal blood vessels and in the endothelial cells lining the fetal capillaries. These cells are important for the function of the mature placenta but are probably not involved in tissue remodeling. This expression pattern suggests that C-CAM is important for the physiological functions of the placental vasculature.
Much remains to be learned about the physiological and cell biological functions of C-CAM, but available data from other systems agree with the idea that it can have different functions in various cells. The best documented property of C-CAM is its ability to mediate cell-cell adhesion by homophilic binding (
It appears plausible that C-CAM-mediated adhesive interactions between the ectoplacental cone trophoblasts, the spongiotrophoblasts, and the vessel-invading trophoblasts are involved in development of the placental tissue structure. C-CAM probably does not contribute to strong intercellular bonds in the same way as cadherins, because it was not localized in close cellular contacts but in loosely organized contact regions with extensive microvillar structures. Microvillar localization of C-CAM has been observed in several other cell types (
Another possibility is that C-CAM's major function in the developing placenta involves signal transduction, which may regulate both proliferative and secretory activities of the trophoblasts. It has indeed been found that C-CAM1 is a signal transduction molecule that can bind protein tyrosine kinases, e.g., c-src (
The function of C-CAM in the cells lining the vessel walls of the mature placenta is probably not mediated by cell-cell contacts, since C-CAM was preferentially found on their free apical surfaces. However, intervillar contacts are still a possibility in these locations. A likely role for C-CAM in these cells is regulation of secretory processes, but it might also influence proliferatory activity.
All tissues and cells in which C-CAM has been found express both C-CAM1 and C-CAM2 simultaneously. This was also found in the placenta throughout its development. In most cell types the shorter isoform, C-CAM2, dominates. The PCR data of the present investigation, however, indicated that the two C-CAM isoforms were expressed at fairly equal levels in the placenta. This is interesting because there are indications that not only the expression levels but also the ratio between C-CAM1 and C-CAM2 are of functional importance. One possibility is that C-CAM2 regulates the activity of the cytoplasmic domain of C-CAM1. The recent finding that C-CAM can form dimers (
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Acknowledgments |
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Supported by the Swedish Medical Research Council (project number 05200), the Petrus and Augusta Hedlunds Foundation and the Karolinska Institute, and by a grant-in-aid for the Science Research Promotion Fund from the Japan Private School Promotion Foundation.
We thank Mr Isao Naito for photographic assistance and Ms Hideko Shimizu and Ms Hiyomi Murakami for technical assistance.
Received for publication December 3, 1996; accepted January 7, 1997.
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