Mol. Hum. Reprod. Advance Access originally published online on May 18, 2005
Molecular Human Reproduction 2005 11(6):429-435; doi:10.1093/molehr/gah183
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Expression of adamalysin 19/ADAM19 in the endometrium and placenta of rhesus monkey (Macaca mulatta) during early pregnancy
1State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100080 and 2Graduate School of the Chinese Academy of Sciences, Beijing 100039, China and 3Department of Chemistry and Biochemistry, Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306-4390, USA
4 To whom correspondence should be addressed at: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 25 Beisihuan Xi Lu, Haidian district, Beijing 100080, China. Email: zhuc{at}ioz.ac.cn
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Abstract |
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A disintegrin and metalloproteinase (ADAM) 19 may contribute to multiple processes including proteolysis, adhesion and intracellular signalling. These processes are also critical for embryo implantation. The aim of this study was to investigate the spatio-temporal expression of the ADAM19 in rhesus monkey uteri on days 12, 18 and 26 of pregnancy. The results showed that in the cloned monkey 346 bp ADAM19 gene fragment and 114 amino acid residues were 98 and 100% identical to those of human homologues, respectively. In-situ hybridization confirmed that the ADAM19 mRNA was located in the luminal and glandular epithelium on day 12 of pregnancy. On day 18 of pregnancy, strong signals of the ADAM19 mRNA were detected in the placental villi, trophoblastic column and glandular epithelium near the myometrium. Moderate expression of the ADAM19 mRNA was seen in the trophoblastic shell and stromal cells. The placental villi and trophoblastic column expressed abundant ADAM19 mRNA, and ADAM19 transcripts were also detected in the trophoblastic shell and fetal–maternal border on day 26 of pregnancy. The expression pattern of the ADAM19 protein was similar to its transcript, but signals for the ADAM19 protein in the stromal cells and trophoblastic shell increased more than its mRNA on day 18 of pregnancy. Statistical analysis demonstrated that the expression level of ADAM19 significantly increased on day 18 of pregnancy. These data suggest that the ADAM19 may be involved in the key processes of glandular secretion, trophoblast invasion and degradation of extracellular matrix during early pregnancy.
Key words: ADAM19/early pregnancy/endometrium/placenta/rhesus monkey
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Introduction |
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The ADAMs (a disintegrin and metalloproteinase, adamalysin) are a large family of transmembrane glycoproteins (Seals and Courtneidge, 2003
). To date, more than 30 ADAMs have been identified in worms, flies, rodents, primates and humans (Wolfsberg et al., 1995; Seals and Courtneidge, 2003). Although the number of ADAM family members has grown rapidly, the biological functions of most members remain to be clarified. Their domain structures suggest that they may be involved in proteolysis (Kang et al., 2002), adhesion (Cal et al., 2000; Gutwein et al., 2000), fusion (Yagami-Hiromasa et al., 1995) and intracellular signalling (Iba et al., 2000).
ADAM19, also referred to as meltrin ß or metalloproteinase/ disintegrin/cysteine-rich (MDC) ß has been identified in both mice and humans (Inoue et al., 1998; Fritsche et al., 2000; Wei et al., 2001). Like most ADAMs, The ADAM19 has a signal sequence, a prodomain with an unpaired cysteine residue (the ‘cysteine-switch’ residue), a metalloproteinase domain with a zinc-binding site, a disintegrin domain, a cysteine-rich domain, an epidermal growth factor-like domain, a transmembrane domain and a cytoplasmic domain with putative SH3 ligand binding sites (Zhao et al., 2001). Previous studies have demonstrated that high levels of the human ADAM19 mRNA were expressed in the placenta, heart, brain, lungs, bladder, spleen, appendix, colon, lymph nodes and skeletal muscle (Wei et al., 2001), but most biological functions of ADAM19 are not fully understood. Because human ADAM19 contains a metalloproteinase domain with a typical zinc-binding consensus sequence, which plays an important role in the degradation and remodelling of extracellular matrix (ECM), it may potentially function in the process of ECM turnover (Zhao et al., 2001). Wei et al. (2001) have reported that the human ADAM19 is an active metalloproteinase using an 
-2-macroglobulin (-2-M) trapping assay. ADAM19 may also possess roles in the processing of neuregulin (Shirakabe et al., 2001), osteoblast differentiation (Inoue et al., 1998), embryo development (Kurisaki et al., 1998) and as a marker for dendritic cell differentiation (Fritsche et al., 2000).
Embryo implantation is a complex physiological process, beginning with blastocyst adhesion to the luminal epithelium and terminating with placenta formation (Carson et al., 2000). Synchronization between the development of the blastocyst and the modifications in the endometrium is necessary for successful implantation (Duc-Goiran et al., 1999). A series of key events must occur during implantation, including apposition and adhesion of the blastocyst to the uterine epithelium, intrusion of placental villi into the endometrium, formation of new vessels, degradation and remodelling of ECM and glandular secretion (Carson et al., 2000). Because the key implantation events are very similar between primates and humans, the rhesus monkey is an ideal animal model for studying the mechanisms of human implantation. Numerous studies have demonstrated that the trophoblast invasion shares many invasive characteristics with tumours (Murray and Lessey, 1999; Janneau et al., 2002), and many ADAMs are believed to support tumour cell adhesion and tumour invasion (Iba et al., 1999; O'Shea et al., 2003). Whether ADAM19 plays crucial roles in ECM turnover, blastocyst adhesion and placental villi invasion during early pregnancy is still unclear. Therefore, in the present study, the spatio-temporal expression of ADAM19 in rhesus monkey endometrium and placenta during early pregnancy was studied using RT–PCR, in-situ hybridization (ISH) and immunohistochemistry.
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Animals and tissue collection
Twelve female rhesus monkeys (Macaca mulatta) with records of normal menstrual cycles and pregnancy were obtained from the Center of Medical Primates, Institute of Medical Biology, Chinese Academy of Medical Sciences. Pregnancy diagnosis was conducted as previously described (Wang et al., 2001
). All experimental protocols were in accordance with the policy of the Ethical Committee, State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences. On estimated days 12, 18 and 26 of pregnancy, the uteri were collected from rhesus monkeys under ketamine hydrochloride anaesthesia. Four samples were included at every stage of pregnancy. The implantation site was located and divided into two sections. One section was fixed in Bouin's solution for 24 h and embedded in paraffin. Endometrium and placenta from the other section were isolated and snap-frozen in liquid nitrogen, and then stored at –80°C for RNA extraction.
Rhesus monkey ADAM19 gene fragment cloning and RT–PCR
The presence of ADAM19 mRNA in macaque endometrium and placenta was examined by RT–PCR. Total RNA from the endometrium and placenta was isolated using Trizol reagent (Gibco-BRL, Grand Island, NY, USA). RT–PCR was conducted according to the previous protocols (Wang et al., 2004). Specific PCR primer pairs used in this study were as follows: (1) ADAM19, sense: 5'-TGCCCATTGACACCACTAT-3' and antisense: 5'-GCTACCACAGGACCCACA-3', giving a 346 bp PCR product; (2) ß-actin, sense: 5'-GTGGGGCGCCCCAGGCACCA-3' and antisense: 5'-CTCCTTAATGTCACGCACGATTTC-3' to amplify a 548 bp PCR product. The optimal ranges of PCR amplification observed were 32 cycles for ADAM19 and 28 cycles for ß-actin. The PCR reaction was carried out by denaturing at 94°C for 45 s, annealing at 59°C for 45 s and extending at 72°C for 45 s. Several control reactions were performed to confirm the quality of RT products and to exclude genomic contamination. Amplification of ß-actin gene transcripts was used to confirm RNA integrity and efficiency. The purified PCR products were cloned into pGEM@-T Easy vector (Promega Corp., Madison, WI, USA) and sequenced to confirm sequence identity (Sangon Corp., Shanghai, China).
In-situ hybridization
Probe generation was performed according to the instructions of digoxigenin RNA labelling Mix (Roche Molecular Biochemical Corp., Mannheim, Germany). Probe labelling efficiency was confirmed by dot blot. The detailed steps for ISH were as described previously (Wang et al., 2004). After extensive removal of paraffin and digestion, the sections (thickness, 5 µm) were prehybridized with a prehybridization solution at 50°C for 2 h, and then hybridized with 400 ng/ml of the labelled antisense or sense probe in prehybridization buffer overnight at 58°C. All slides were completely washed and incubated with anti-DIG-alkaline phosphatase antibody (diluted 1:500) for 2 h. The colour was produced by nitroblue tetrazolium chloride and 5-bromo-4-chloro-3-indolyl phosphate (NBT/BCIP, Roche). Sense probe hybridizations were performed as a control for the background level. The results were recorded with a SPOT digital camera system (Diagnostic Instruments, Inc., Sterling Heights, MI, USA), and the digital images were processed by Adobe PhotoShop (Version 7.0; Adobe, San Jose, CA, USA).
Immunohistochemistry
The anti-human ADAM19 polyclonal antibody against metallo-domain was developed by Zhao et al. (2001). Immunohistochemistry was performed using the HistostainTM-Plus Kit and DAB Kit (Zhongshan Corp., Beijing, China), as recommended by the manufacturer. In brief, the paraffin-embedded sections (thickness, 5 µm) were dewaxed completely and treated with 3% H2O2 in methanol for 15 min to inhibit endogenous peroxidase activity. In order to expose the antigens sufficiently, the slides were immersed in citric acid buffer (10 mmol/l citrate sodium and 10 mmol/l citric acid, pH 6) and boiled in a microwave oven at 92–98°C for 15 min. After cooling to room temperature, the sections were then sequentially incubated at room temperature with normal blocking serum for 20 min, human ADAM19 antibody (15 µg/ml) for 3 h, biotinylated secondary antibody for 20 min and streptavidin peroxidase for 15 min. Intervening phosphate-buffered saline washes were performed as necessary. The sections were then stained with 3,3'-diaminobenzidine and counterstained with haematoxylin. Substitution of preimmune serum for the primary antibody was utilized as negative control.
Statistical analysis
The relative intensity of the PCR products was determined by densitometric analysis of band intensities. The bands were analysed using the MetaView Image Analysing System (Version 4.50; Universal Imaging Corp., Downingtown, PA, USA). The relative level of ADAM19 mRNA normalized to ß-actin mRNA was calculated. Signal intensities of the ADAM19 mRNA and protein detected by ISH and immunohistochemistry were quantified by computer-aided laser scanning densitometry (Personal Densitometer SI; Molecular Dynamics Inc., Sunnyvale, CA, USA). Statistical methods were as described previously (Wang et al., 2004). One-way analysis of variance was used to evaluate the RT–PCR data and the average intensity data from both ISH and immunohistochemistry. The general linear model was used to analyse the difference in different locations within time points and different time points within locations. Differences were considered significant at P<0.05.
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Temporal expression of ADAM19 mRNA in the rhesus monkey uterus
RT–PCR was used to detect the expression and variation of the ADAM19 mRNA in the macaque uterus on days 12, 18 and 26 of pregnancy. Representative illustrations of PCR products, graphical statistical analysis and a sequence comparison are shown in Figure 1. As shown in Figure 1A, a 346 bp fragment of the ADAM19 gene and a band of 548 bp representing the ß-actin gene were obtained from each sample at every stage of pregnancy. No specific bands were found in negative controls in the PCR system (data not shown). A densitometric analysis revealed the highest expression of the ADAM19 mRNA on day 18 of pregnancy (P<0.05) (Figure 1B). The identity of the ADAM19 PCR products was confirmed by sequencing. There was 98% sequence identity of the rhesus monkey ADAM19 fragment to the human ADAM19 gene (nt 1805 to 2150, Genbank accession no. AF311317 [GenBank] ), as seven point variations were found in the macaque 346 bp ADAM19 gene fragment when compared with the human homologue. The sequence of 114 amino acid residues encoded by the macaque ADAM19 fragment was identical to that of the human homologue (Figure 1C).
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Localization of ADAM19 mRNA in the rhesus monkey endometrium and placenta during early pregnancy
The spatio-temporal expression of the ADAM19 mRNA in the pregnant macaque uterus was studied by ISH. As shown in Figure 2 and Table I, ADAM19 mRNA was mainly located in the luminal and glandular epithelium on day 12 of pregnancy (P<0.05), while faint ADAM19 mRNA was found in the stromal cells (Figure 2, D12). On day 18 of pregnancy, strong ADAM19 mRNA signals were detected in the placental villi, trophoblastic column and glandular epithelium situated adjacent to the myometrium (P<0.05), while moderate expression of the ADAM19 mRNA was found in the trophoblastic shell and stromal cells (Figure 2, D18). ADAM19 transcripts concentrated in the placental villi and trophoblastic column (P<0.05), and moderate ADAM19 mRNA signals were found in the trophoblastic shell and fetal–maternal border on day 26 of pregnancy (Figure 2, D26). Statistical analysis revealed that the average intensity of ADAM19 mRNA was the highest on day 18 of pregnancy (P<0.05) (Table I). ADAM19 mRNA was absent in the myometrium on days 12, 18 and 26 of pregnancy (Figure 2, D18 and D26). Control sections hybridized with sense probe showed only low background staining on day 18 (Figure 2, Control).
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Immunohistochemical staining of ADAM19 protein in the pregnant macaque endometrium and placenta
The expression pattern of the ADAM19 protein was similar to that of ADAM19 mRNA. As shown in Figure 3, abundant ADAM19 protein was expressed in the luminal and glandular epithelium on day 12 of pregnancy (Figure 3, D12), in the placental villi, trophoblastic column, trophoblastic shell, glandular epithelium and stromal cells on day 18 of pregnancy (Figure 3, D18), and in the placental villi and trophoblastic column on day 26 of pregnancy (P<0.05) (Figure 3, D26). Furthermore, moderate signals of ADAM19 protein were detected in the stromal cells on day 12 of pregnancy, and in the trophoblastic shell and fetal–maternal border on day 26 of pregnancy (Figure 3, D12 and D26). The glandular epithelium and stromal cells showed weak ADAM19 protein staining on day 26 of pregnancy (Figure 3, D26). Only faint signals of ADAM19 protein were detected in the myometrium at any time point during pregnancy (Figure 3, D12 and D18). Statistical results compiled in Table II demonstrate that the average intensity of ADAM19 protein was the highest on day 18 of pregnancy (P<0.05), and the intensity of ADAM19 protein in the stromal cells and trophoblastic shell increased more than its mRNA on day 18 of pregnancy. Control sections substituting preimmune serum for the primary antibody did not produce any positive immunostaining signals for ADAM19 protein (Figure 3, Control).
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Discussion |
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Implantation begins when the blastocyst assumes a fixed position in the uterus and establishes a more intimate relationship with the endometrium (Duc-Goiran et al., 1999
). The interaction between an activated blastocyst and a receptive uterus is an important component of a complex process that leads to the successful implantation and the early stages of placental development (Norwitz et al., 2001). Successful implantation and early pregnancy depends on a series of key events and conditions that include blastocyst adhesion, endometrium receptivity, placental villi invasion, extensive degradation and remodelling of ECM, angiogenesis and glandular secretion (Carson et al., 2000). ADAM19 is a new member of the ADAM family and an active metalloproteinase. Like other ADAM family members, ADAM19 is a MDC transmembrane glycoprotein (Zhao et al., 2001). ADAM19 has also been verified to possess proteolytic activity following its activation by furin-like proprotein convertases (Zhao et al., 2001; Kang et al., 2002). Although previous studies have demonstrated that the ADAM19 is highly expressed in the human placenta and also plays a role in murine embryo development (Kurisaki et al., 1998; Wei et al., 2001), little is known about the role of ADAM19 in embryo implantation. Therefore, in this report we provide the spatio-temporal expression of ADAM19 in rhesus monkey endometrium and placenta on days 12, 18 and 26 of pregnancy, and explore the involvement of ADAM19 in early pregnancy. ADAM19 mRNA was detected on days 12, 18 and 26 of pregnancy by RT–PCR. Statistical analyses revealed that the ADAM19 mRNA and protein were both highly expressed on day 18 of pregnancy, and these results suggest that ADAM19 may be involved in early pregnancy. Sequence identification revealed that both the ADAM19 gene fragment and the amino acid residues of the rhesus monkey had high sequence identity with their human homologues, so the results from this study are helpful to explore the mechanisms of human implantation.
Although the significance of ADAM19 in the endometrium epithelial cells is not presently clear, the uterine secretory substances from the endometrial glands are essential for uterine receptivity and successful implantation (Gray et al., 2001). As ADAM19 was expressed in the luminal and glandular epithelium at the early stage of pregnancy, it is possible to propose a role in secretory function for ADAM19 during early pregnancy. Furthermore, the competence of trophoblast invasion is critical for successful implantation. Trophoblast penetration into the endometrium may be considered analogous to invasion by tumour cells (Bischof and Campana, 2000; Janneau et al., 2002). The trophoblast invades the endometrium by proteolysis of the underlying basement membrane and ECM components of the stroma (Kim et al., 1999). Some ADAMs have been verified to function in tumour cell invasion (McCulloch et al., 2000; O'Shea et al., 2003). Like matrix metalloproteinase family members, ADAM19 contains a metalloproteinase domain capable of proteolytic activity (Kang et al., 2002). The proteolytic activity of soluble forms of ADAM19 was achieved by their autocatalytic removal of a purification tag (Myc-His) and their ability to cleave myelin basic protein (Chesneau et al., 2003). Placentation will be complete by day 26 of pregnancy (Enders et al., 1997; Enders and Lopata, 1999). Thus, day 18 of pregnancy is a critical period for implantation, during which a series of morphological, biochemical and immunological changes will occur in the endometrium and placenta (Cross et al., 1994). Because high levels of ADAM19 were found in the placental villi, trophoblastic column, trophoblastic shell and stromal cells on days 18 and 26 of pregnancy, it is reasonable to infer that ADAM19 may be involved in trophoblast invasion and ECM degradation at the medius and late stages of implantation, particularly during the most critical period of implantation (day 18 of pregnancy). Another interesting finding of this study is that the signals for ADAM19 protein in the stromal cells and trophoblastic shell increased more than its mRNA on day 18 of pregnancy. The ADAM19 expression difference between mRNA and protein is possibly due to the different regulatory mechanisms of mRNA transcription and protein translation. The increasing expression of ADAM19 protein in the stromal cells and trophoblastic shell on day 18 of pregnancy provides further evidence that the ADAM19 is probably responsible for ECM degradation and trophoblast invasion. From the results presented herein, we suggest that ADAM19 plays different roles at the different stages of early pregnancy.
In conclusion, we report here the spatio-temporal expression of ADAM19 in rhesus monkey endometrium and placenta during early pregnancy. The presence of ADAM19 in the luminal and glandular epithelium, placenta and stromal cells raises the possibility that ADAM19 is involved in glandular secretion, trophoblast invasion and the degradation of ECM. This study will help further investigations as to the precise contributions of ADAM19 to the mechanisms governing embryo implantation.
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Acknowledgements |
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The authors acknowledge Ms Hua Qin for statistical data collection. We are also grateful to Robert G. Newcomer and Dr Qing-Lei Li for critical reading of this manuscript and their helpful suggestions. This work was supported by the Special Funds for Major State Basic Research Project (G1999055903), the CAS Innovation Program (KSCX3-IOZ-07), the Florida State University Developing Scholar Award (to Q.-X. S.) and FSU Research Foundation Program Enhancement Grants (to Y.-G. Z. and Q.-X. S.).
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Submitted on March 8, 2005; accepted on April 25, 2005.
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