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Biology of Reproduction 63, 1781-1786 (2000)
© 2000 Society for the Study of Reproduction, Inc.

Regular Article

Detection of Multiple Bone Morphogenetic Protein Messenger Ribonucleic Acids and Their Signal Transducer, Smad1, During Mouse Decidualization1

Ying Ying a, and Guang-Quan Zhao2,a

a Department of Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, Missouri 65211

ABSTRACT

Decidualization is a process characterized by morphological and functional changes in the uterine stromal cells. In addition to steroid hormones, growth factors are implicated in this process. Using in situ hybridization, we found that mRNAs for several bone morphogenetic proteins (BMPs) were detected in the decidual and vascular endothelial cells. The Bmp7 mRNA was detected in the decidualizing stromal cells surrounding the blastocyst and distributed in a gradient, with the highest levels occurring near the uterine epithelium at 4.5 days post-coitus (dpc). With the progression of decidualization, Bmp7 signals in the deciduum at the antimesometrial side decreased, but strong signals were retained in the decidual area at the mesometrial side at 7.0 dpc. In contrast, Bmp8a transcripts increased from 5.5 to 7.0 dpc in the decidual tissue, with the highest levels occurring in the secondary decidual zone at the antimesometrial side. The Bmp2, Bmp4, and Smad1 transcripts were found in the secondary decidual zone, especially at the mesometrial side. The Bmp2 signals were primarily detected in decidual cells, whereas Bmp4 and Smad1 transcripts were mainly detected in vascular endothelial cells, suggesting that they may be involved in decidual angiogenesis.

decidua, growth factors, implantation/early development, signal transduction, uterus

INTRODUCTION

Implantation establishes the connection between the embryo and maternal uterus. At the beginning of this process, the blastocyst trophectoderm attaches the receptive uterine epithelium and initiates transformation of endometrial stromal cells into decidual cells (decidual cell reaction). Decidualization is a process with characteristics of morphological and functional changes in the stromal cells, including tissue swelling and vascular remodeling. Although decidualization occurs mainly under the influence of ovarian steroid hormones [1–3], several growth factors are involved in this process [4, 5]. For example, decidualized stromal cells produce a variety of growth factors, including fibroblast growth factor, epidermal growth factor, and insulin-like growth factor-binding protein 1 [6–8]. With decidual growth, many other factors, such as vascular endothelial growth factor and transforming growth factors (TGF)-{alpha} and -ß, are also implicated in decidual cell proliferation, apoptosis, and angiogenesis [4, 5, 9–12].

Bone morphogenetic proteins (BMPs) are pleiotropic growth and differentiation factors belonging to the TGF-ß superfamily [13]. More than 20 BMPs have been identified in species ranging from C. elegans to humans [13, 14]. Based on sequence homology, BMPs are grouped into several subgroups [13, 14], of which the DPP and 60A subfamily are the best characterized. The former includes Drosophila DPP and vertebrate BMP2 and BMP4 [13]. The 60A group includes the Drosophila 60A protein and the vertebrate BMP5, BMP6, BMP7, BMP8A, and BMP8B proteins [13, 15]. The BMPs play a variety of roles in cell proliferation, differentiation, survival, and fate determination[15–19].

The BMPs function as homodimers or heterodimers by binding to heteromeric receptor complexes that contain type I and type II serine/threonine kinase receptors [20]. Both receptor types are required for signal transduction [13, 20]. Several putative receptors for BMPs have been identified, including BMP receptors type IA (ALK3), type IB (ALK6), and type II (TALK) [21, 22]. On ligand binding, type II receptors phosphorylate type I receptors, which in turn phosphorylate SMADs, a group of proteins responsible for intracellular signal transduction of the TGF-ß superfamily [23]. The SMADs are divided into three subgroups: ligand-responsive SMADs, including SMAD1, SMAD2, SMAD3, SMAD5 and SMAD8 [24–26]; a common signaling partner SMAD4 [27]; and inhibitory SMADs, such as SMAD6 and SMAD7 [28, 29]. Whereas SMAD1, SMAD5 and SMAD8 mediate BMP signaling [25, 26], activated SMAD1 forms a heteromeric complex with SMAD4 and is then translocated into the nucleus [20, 27].

The BMPs exert various effects on many tissues in addition to inducing bone and cartilage formation [13]; however, relatively little is known regarding the role of BMPs in the decidual cell reaction during normal implantation. Ozkaynak et al. [30] reported that Bmp7 mRNA was detected in the endometrium of the mouse uterus and declines during pregnancy. Moreover, its transcript level was downregulated by estrogen. Other studies have also found Bmp2, Bmp4, and Bmp8a mRNAs in mouse decidua [31, 32]. To better understand the functions of Bmp genes in the decidulization, we used in situ hybridization to investigate the spatial and temporal distribution patterns of mRNAs for the 60A subfamily members (Bmp7 and Bmp8a), the Dpp subfamily members (Bmp2 and Bmp4), and their downstream mediator (Smad1) during the decidualization in the mouse.

MATERIALS AND METHODS

Animals

Adult male and female ICR mice were bred randomly and maintained in the Animal Science Center at the University of Missouri-Columbia under a controlled environment with a photoperiod of 13-h light (0800–2100 h) and 11-h dark, a humidity of 50%, and a temperature ranging from 70–75°F. Food and tap water were available ad libitum. To set up mating, a female mouse was caged with a male mouse overnight. Noon on the day of the copulation plug being found was designated as 0.5 days post-coitus (dpc).

Tissue Preparation

Pregnant females at 4.5–7.0 dpc were killed by cervical dislocation. Uteri were removed to isolate implantation sites, which were fixed in 4% paraformaldehyde in PBS for 4–12 hours at 4°C. After dehydration in increased concentrations of ethanol, specimens were embedded in Paraplast (Fisher Scientific, Pittsburgh, PA). Next, 7 µm-thick sections were serially cut. The sections were mounted onto Superfrost Plus slides (Fisher Scientific) for in situ hybridization [32].

Hybridization Probes

For in situ hybridization, both sense and antisense single-stranded RNA probes were generated from linearized plasmids in the presence of {alpha}-35S-uridine triphosphate using T3, T7, or SP6 RNA polymerase (Promega, Madison, WI) to a specific activity of 1.0 x 109 cpm/µg. The probes used in this study included mouse Bmp2, Bmp4, Bmp7, Bmp8a, and Smad1 as reported elsewhere [16–19, 33].

In Situ Hybridization

In situ hybridization was performed essentially as described elsewhere [32]. In brief, deparaffinized sections were dehydrated in graded ethanol and rinsed with PBS three times. After incubation with 20 µg/ml of proteinase K in PBS for 5–8 min, sections were refixed in 4% paraformaldehyde in PBS for 15 min at room temperature. After being washed with PBS, slides were acetylated with freshly prepared, 0.2 M triethanolamine containing 0.25% acetic anhydride for 5 min. Hybridization was performed at 60–6°C for 16–20 h in a mixture containing 2 x 104 cpm/µl of RNA probes (either sense or antisense), 300 mM NaCl, 10 mM Tris-HCl, 10 mM NaH2PO4, 5 mM NaEDTA, 0.2% Ficoll 400, 0.2% polyvinyl pyrrolidone, 50 mM dithiothreitol, 10% dextran sulfate, 50% deionized formamide, and 100 µg/ml of yeast tRNA. The slides were washed twice with 2x saline sodium citrate (SSC), 50% formamide, and 20 mM ß-mercaptoethanol at 60–65°C for 30 min. After additional washing with 2x SSC and 2 mM EDTA at 37°C for 10 min, the sections were treated with 20 µg/ml of RNase A in 2x SSC and 2 mM EDTA at 37°C for 30 min. The slides were finally rinsed with distilled water and air-dried. Autoradiography was performed using NTB-2 Kodak emulsion (Eastman Kodak, Rochester, NY), and the slides were exposed for 40 h (Bmp2) or 1 wk (all other probes) at 4°C. After development, the slides were stained with Mayer hematoxylin for 1–2 min and then mounted with Permount (Fisher Scientific). Photomicrographs were taken with both light- and dark-field optics.

RESULTS

Temporal and Spatial Distribution Pattern of Bmp7 mRNA During Decidualization

Previous investigation demonstrated that Bmp7 mRNA was detected in both epithelial and subjacent stromal cells of the nonpregnant mouse uterus [30]. Results of Northern hybridization studies showed that Bmp7 transcripts were also detected in the uterus of the pregnant mouse before 8.0 dpc [30]. To address the possible role of Bmp7 in the decidual cell reaction, we examined the temporal and spatial pattern of Bmp7 mRNA in the mouse deciduum using in situ hybridization with antisense RNA probe against the Bmp7 mRNA. As shown in Figure 1, A–C, which depicts a transverse section of one uterine horn, the embryo was seen to implant at the antimesometrial aspect of the uterus (i.e., in the wall distal to the broad ligament), and decidualization was obvious in the surrounding stroma. The Bmp7 mRNA was detected in the stromal tissue surrounding the embryo (Fig. 1, A and B). Signals were detected in the decidualizing stromal cells and distributed in a gradient, with highest levels occurring near the uterine epithelium (Fig. 1B). The Bmp7 signals were not observed at a significant level in the embryos and uterine epithelial cells at this stage (Fig. 1C). At 5.5 dpc, a proamniotic cavity was formed in the egg cylinder, and the ectoplacental cone began to form (Fig. 1D). High levels of Bmp7 mRNA were still detectable in the decidual cells adjacent to the embryo at both mesometrial and antimesometrial sides (Fig. 1, D and E), especially in the area near the ectoplacental cone (Fig. 1, E and F), but not at the embryo itself (Fig. 1F). With the progression of decidualization, Bmp7 signals in the deciduum at the antimesometrial side decreased, but strong autoradiographic signals were retained at the mesometrial side (Fig. 1, G–I).



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  		FIG. 1. In situ hybridization showing spatial and temporal distribution pattern of Bmp7 mRNA in the mouse uterus during implantation. Brightfield photographs (A, D, and G) and corresponding darkfield photographs (B, E, and H) were sections of the decidua hybridized with an antisense RNA probes against Bmp7 mRNA. Brightfield pictures at high magnification (C, F, and II) show Bmp7 transcripts in the decidual cells. dc, Decidual cells; ddc, dying decidual cells; ex, extraembryonic ectoderm; gtb, giant trophoblast cells; icm, inner cell mass; me, mesometrial side; tb, trophoblast; ue, uterine epithelium. Bar = 70 µm in A, B, D, E, G, and H and 15 µm in C, F, and I

Different Distribution Patterns of Bmp8a and Bmp2 mRNAs in the Deciduum

As mentioned, BMP7 belongs to the 60A class of BMP superfamily [13]. Other members in this class include BMP5, BMP6, BMP8A, and BMP8B [13, 15]. Zhao and Hogan [32] previously reported that Bmp8a mRNA was accumulated in the decidual cells. Coucouvanis and Martin [31] showed that mRNA for Bmp2, which is a member of the Dpp subfamily, was also detected in the maternal decidual tissue. Here, we further compared Bmp8a and Bmp2 in situ hybridization patterns. No strong Bmp8a in situ hybridization signal was detected in the deciduum and uterus before 5.5 dpc [32]. Signals in the deciduum increased from 5.5 to 7.5 dpc (data not shown). As shown in Figure 2, the highest level of Bmp8a mRNA was mainly observed in the decidual tissue, at a distance from the conceptus on the antimesometrial side at 7.0 dpc (Fig. 2, A–D), and Bmp8a transcripts in the deciduum continued to 10.5 dpc [32]. Lower levels of signals were also noted in the mesometrial region of the deciduum. The Bmp8a mRNA was not detectable in decidual cells immediately surrounding the conceptus, where Bmp7 mRNAs were most abundant. Therefore, Bmp8a and Bmp7 mRNAs appear to have complimentary distribution. The Bmp2 mRNA can be detected in the decidual cells at 5.5 and 6.5 dpc [31]. At 7.0 dpc, Bmp2 transcripts were primarily found in the decidual tissue at a considerable distance from the embryo (Fig. 2, E–H). The highest levels of signals were observed in the mesometrial region of the deciduum (Fig. 2, E–H), where more blood vessels are formed. Such a distribution pattern is opposite to that of Bmp8a (Fig. 2, A–D).



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  		FIG. 2. The Bmp8a and Bmp2 transcripts in mouse decidua at 7.0 dpc by in situ hybridization. A–D) Brightfield (A and C) and darkfield (B and D) photographs of sections of decidua hybridized with antisense probe against Bmp8a mRNA. E–H) Brightfield (E and G) and darkfield (F and H) photographs of sections of decidua hybridized with an antisense probe against Bmp2 mRNA. I) Positions of the sections. Asterisks mark the positions of embryos. me, Mesometrial side; pc, ectoplacental cone. Bar = 140 µm

Bmp4 and Smad1 mRNAs in Vascular Endothelial Cells During Decidualization

Not only are Bmp2 and Bmp4 equally related to dpp, which is the Drosophila counterpart of these genes [13, 14], but in certain experimental systems, BMP2, BMP4 and DPP are functionally interchangeable [31, 34]. Therefore, we further investigated the distribution of Bmp4 mRNA in decidual tissue. At 7.0 dpc, Bmp4 had the highest levels at the mesometrial side. Unlike Bmp2 transcript, which was mainly found in decidual cells and not in the vascular endothelial cells (Fig. 3, A–C), Bmp4 mRNA had a low level in the decidual cells but much higher levels in the vascular endothelial cells (Fig. 3, D–F). To further address the BMP signaling pathway in decidualization, we examined the presence of mRNA for Smad1, which is a downstream member of BMP signaling cascades. As shown in Figure 3, G–I, at 7.0 dpc high levels of Smad1 transcripts were noted in vascular endothelial cells, which is a pattern similar to that of Bmp4.



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  		FIG. 3. Comparison of Bmp2, Bmp4, and Smad1 mRNA distribution patterns in mouse decidua at 7.0 dpc. Left) Brightfield photographs of sections of decidua showing the decidual area at the mesometrial side. Middle) Corresponding darkfield photographs. Right) High-magnification photographs showing Bmp2, Bmp4, and Smad1 transcripts at cellular levels. The Bmp2 signals were primarily detected in the decidual cells (dc). The Bmp4 signals were detected at high levels in the vascular endothelial cells (en) and at low levels in the decidual cells. The Smad1 transcripts were mainly found in the vascular endothelial cells. Bar = 70 µm in A, B, D, E, G, and H and 10 µm in C, G, and I

DISCUSSION

Although decidualization of the uterine stroma is primarily directed by two steroid hormones, estrogen and progesterone, the molecular and cellular mechanisms involved in this process are far from clear. Recent investigations have demonstrated that several growth factors and their receptors are expressed in the decidual stroma and vascular endothelial cells [4, 5], suggesting that the effects of hormones may be mediated by these growth factors. Here, we showed that multiple BMP mRNAs are detected in the mouse deciduum in spatially and temporally unique patterns. Whether products of these Bmp mRNAs are essential for embryo implantation is not clear, but observations of decidual and vascular endothelial cell-specific accumulation of some Bmp mRNAs suggest that BMPs may play a role in the decidual cell reaction and angiogenesis.

In mice and rats, the deciduum develops from uterine stromal cells and completely surrounds the postimplantation embryos at each implantation site. Previous study showed that Bmp7 mRNA was mainly detected in the uterine epithelium in the nonpregnant mouse [30]. Here, we demonstrated it in decidual cells surrounding the embryo shortly after implantation, but not in uterine epithelial cells. In addition, the appearance of Bmp7 mRNA is temporally and spatially correlated with the progression of implantation, indicating that the implanting embryo may induce the expression of Bmp7 in the decidual tissue. Interestingly, Bmp7 transcripts gradually decrease in the deciduum at the antimesometrial side from 4.5 to 7.0 dpc (Fig. 1, A–H); they are mainly located in the primary decidual zone at the mesometrial side at 7.0 dpc (Fig. 1, G and H). This pattern suggests that Bmp7 may be involved in the stromal cell proliferation at the beginning of decidual cell reaction; later, it may play a role in the trophoblast invasion and decidual cell death. In contrast, Bmp8a mRNAs gradually increase during this period of time [32], and they are mainly found in the secondary decidual zone at the antimesometrial side, which is temporally and spatially complimentary to the Bmp7 pattern.

Multiple signaling molecules, including fibroblast growth factor-2 [35], vascular endothelial growth factor [36], angiopoietin-1 [37], platelet-derived growth factor [38], ephrin-B2 [39], and TGF-ß1 [40], are implicated in angiogenesis. Several factors stimulating and inhibiting angiogenesis have been identified in the endometrium and decidua, but how these factors cooperate to produce the tightly controlled, hormonally regulated angiogenesis is not known [41]. Here, we found that Bmp2 and Bmp4 mRNAs were mainly detected in the secondary decidual zone at the mesometrial side at 7.0 dpc, where many blood vessels are being generated. Thus, speculating that both may be required for angiogenesis seems reasonable. This hypothesis is also supported by the observation that transcripts for Smad1, a downstream intracellular mediator of the BMP signaling pathway, are found in the vascular endothelial cells at the mesometrial side. Other studies have demonstrated that growth/differentiation factor 5, which is a member of the BMP family, can induce angiogenesis in both chick chorioallantoic membrane and rabbit cornea assays [42]. In addition, Smad5, another member of the downstream mediators in the BMP signaling pathway, is required for yolk sac angiogenesis in the mouse [43]. These observations indicate that the BMP signaling transduction pathway may be involved in the angiogenesis during decidualization. That Bmp2 signals are primarily detected in the decidual cells adjacent to the vascular endothelial cells (Fig. 3C), whereas Bmp4 transcripts along with Smad1 are mainly noted in the vascular endothelial cells (Fig. 3, F and I), suggests that these two ligands function as the autocrine and short-range paracrine factors during angiogenesis.

The BMPs function in many processes of reproduction, including primordial germ cell specification [44, 45], spermatogenesis, and epididymis function [15, 16]. The data presented in this study may suggest that BMP7, produced by the stromal cells subjacent to the embryo, may play a role in initial decidual cell reaction and trophoblast invasion. At 7.0 to 7.5 dpc, when Bmp7 transcription decreases and Bmp8a mRNA begins to accumulate at a high level (Fig. 4A), BMP8A secreted by decidual cells at the secondary decidual zone at the antimesometrial side is recruited to further promote decidualization. At the same time, BMP2 and BMP4 (Fig. 4, B and C) generated by the decidual and endothelial cells at the secondary decidual zone on the mesometrial side promote angiogenesis and decidualization in conjunction with BMP8A and other molecules. These BMPs, as well as other factors, cooperate with the steroid hormones to promote decidualization. Further work is required to test this model and to unveil the effects of BMPs in decidulization and implantation.



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  		FIG. 4. Transcript distribution for Bmps and Smad1 in mouse decidua at 7.0 to 7.5 dpc. A) Patterns of Bmp7 (green) and Bmp8a (blue) in a longitudinal section of the deciduum. B) The Bmp2 mRNA distribution in decidual cells (red). C) The Bmp4 and Smad1 pattern in vascular endothelial cells at the mesometrial side (green). Asterisks mark the positions of embryos

FOOTNOTES

First decision: 22 June 2000.

1 Supported by National Institutes of Health grant HD 36218 and the March of Dimes Basil O'Connor Award. Back

2 Correspondence: Guang-Quan Zhao, 209C Connaway Hall, Department of Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO 65211. FAX: 573 884 5414; zhaog{at}missouri.edu Back

Accepted: July 28, 2000.

Received: May 12, 2000.

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G. Lagna, M. M. Ku, P. H. Nguyen, N. A. Neuman, B. N. Davis, and A. Hata
Control of Phenotypic Plasticity of Smooth Muscle Cells by Bone Morphogenetic Protein Signaling through the Myocardin-related Transcription Factors
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Q. Li, A. Kannan, W. Wang, F. J. DeMayo, R. N. Taylor, M. K. Bagchi, and I. C. Bagchi
Bone Morphogenetic Protein 2 Functions via a Conserved Signaling Pathway Involving Wnt4 to Regulate Uterine Decidualization in the Mouse and the Human
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K. Y. Lee, J.-W. Jeong, J. Wang, L. Ma, J. F. Martin, S. Y. Tsai, J. P. Lydon, and F. J. DeMayo
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G. Lagna, P. H. Nguyen, W. Ni, and A. Hata
BMP-dependent activation of caspase-9 and caspase-8 mediates apoptosis in pulmonary artery smooth muscle cells.
Am J Physiol Lung Cell Mol Physiol, November 1, 2006; 291(5): L1059 - L1067.
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A. Mukherjee, S. M. Soyal, R. Fernandez-Valdivia, M. Gehin, P. Chambon, F. J. DeMayo, J. P. Lydon, and B. W. O'Malley
Steroid Receptor Coactivator 2 Is Critical for Progesterone-Dependent Uterine Function and Mammary Morphogenesis in the Mouse.
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R. L Jones, C. Stoikos, J. K Findlay, and L. A Salamonsen
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E. Dimitriadis, C.A. White, R.L. Jones, and L.A. Salamonsen
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M. Mericskay, J. Kitajewski, and D. Sassoon
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S. Shimasaki, R. K. Moore, F. Otsuka, and G. F. Erickson
The Bone Morphogenetic Protein System In Mammalian Reproduction
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M. Kiyono and M. Shibuya
Bone Morphogenetic Protein 4 Mediates Apoptosis of Capillary Endothelial Cells during Rat Pupillary Membrane Regression
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K. Y. Arai, K. Tsuchida, K. Uehara, K. Taya, and H. Sugino
Characterization of Rat Follistatin-Related Gene: Effects of Estrous Cycle Stage and Pregnancy on Its Messenger RNA Expression in Rat Reproductive Tissues
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R. L. Jones, L. A. Salamonsen, Y. C. Zhao, J.-F. Ethier, A. E. Drummond, and J. K. Findlay
Expression of activin receptors, follistatin and betaglycan by human endometrial stromal cells; consistent with a role for activins during decidualization
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M. W. Geraci, M. Moore, T. Gesell, M. E. Yeager, L. Alger, H. Golpon, B. Gao, J. E. Loyd, R. M. Tuder, and N. F. Voelkel
Gene Expression Patterns in the Lungs of Patients With Primary Pulmonary Hypertension : A Gene Microarray Analysis
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