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RESEARCH |
1 Center for Animal Biotechnology and Genomics and Department of Animal Science and 2 Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA
Correspondence should be addressed to T E Spencer; Email: tspencer{at}tamu.edu
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Introduction |
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Recently, a new galectin family member and component of uterine histotroph, galectin-15, was discovered in the endometrium of sheep (Gray et al. 2004). Galectin-15 was originally identified in ovine intestinal epithelium as being induced in response to infection by Haemonchus contortus, a nematode parasite (Dunphy et al. 2000). Expression of the galectin-15 gene was detected only after day 10 of pregnancy in the endometrial LE and superficial ductal GE (sGE) and was induced by progesterone and further stimulated by interferon 
, the pregnancy-recognition signal produced by the conceptus. In the endometrium, galectin-15 protein had a nucleocytoplasmic distribution within the LE and sGE and was also concentrated near and on the apical surface. Further, secreted galectin-15 protein was abundant in the histotroph recovered from the uterine lumen and was immunologically similar to the previously unknown 14 kDa protein that is a component of crystals in the endometrial epithelium and conceptus trophectoderm (Gray et al. 2004, Kazemi et al. 1990). Galectins bind ß-galactosides and functionally crosslink glycoprotein and glycolipid receptors on the surface of cells, which initiates biological responses that include cell proliferation, differentiation, motility, adhesion and apoptosis (Cooper 2002, Yang & Liu 2003, Liu & Rabinovich 2005). The temporal and spatial alterations in galectin-15 mRNA and protein the uterine endometrial epithelia and lumen during the peri-implantation period of early pregnancy, combined with the known biological activities of other galectins, make it a strong candidate mediator of conceptus–endometrial interactions during implantation (Gray et al. 2004). One proposed extracellular role of galectin-15 in the uterine lumen is to functionally bind and crosslink ß-galactosides on glycoproteins and glycolipids, thereby allowing it to function as a heterophilic cell adhesion molecule bridging the conceptus trophectoderm and the endometrial LE and stimulating biological responses within the trophoblast, such as migration, proliferation and differentiation, which are critical for successful conceptus implantation (Spencer et al. 2004).
Our working hypothesis is that galectin-15 is secreted as a component of histotroph that is secreted by the endometrial epithelia throughout pregnancy in sheep. Therefore, the present study investigated: (1) extracellular and intracellular galectin-15 protein in the uterus and conceptus on days 12 to 16 of pregnancy; (2) galectin-15 mRNA and protein in uteroplacental tissues between days 20 and 120 of pregnancy; and (3) galectin-15 mRNA in the uterus after parturition.
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Study 1
Cyclic ewes were mated at estrus (day 0) to either a vasectomized or an intact ram and were hysterectomized (n = 5 sheep/day) on days 12, 14 or 16 of the estrous cycle or on days 12, 14 and 16 of pregnancy (the gestation period is 147 days). For all surgeries performed, ewes were administered isofluorane (5%) via an inhalation mask to induce anesthesia, which was maintained with isofluorane (1–5%). A midventral laparotomy was performed to expose the reproductive tract. The uterine lumen was flushed with saline and examined for the presence of a morphologically normal conceptus to confirm pregnancy. Uterine flushes were clarified by centrifugation (3000 g for 30 min at 4 °C), aliquoted and frozen at –80 °C. Cross-sections of the uterine horn ipsilateral to the ovary bearing the corpus luteum and conceptuses from day 16 pregnant ewes were fixed for analysis by electron microscopy.
Study 2
As described previously (Kwon et al. 2004), ewes were mated to rams of proven fertility at estrus and 12 and 24 h later. Ewes were assigned randomly to be hysterectomized (n = 4 per day) on day 20, 40, 60, 80, 100 or 120 of gestation to allow collection of uteroplacental tissues and fetal fluids. At hysterectomy, samples of the amniotic and allantoic fluids were collected, snap-frozen in liquid nitrogen and stored at –80 °C. Total endometrium was collected on days 16 and 20 of pregnancy, whereas caruncular and intercaruncular endometria were dissected from the myometrium collected between days 40 and 120 of gestation. Portions of these tissues were snap-frozen in liquid nitrogen and stored at –80 °C. Sections of the uterine wall with the attached trophectoderm were also fixed in freshly prepared 4% (w/v) paraformaldehyde in PBS (pH 7.2) or embedded in Optimal Cutting Temperature (OCT) compound (Miles, Oneota, NY, USA), snap-frozen in liquid nitrogen and stored at –80 °C.
Study 3
As described previously (Gray et al. 2003), multiparous 5–8-year-old ewes were bred with rams of proven fertility, and pregnancy was determined by transabdominal ultrasonography. Ewes were assigned randomly to be ovariohysterectomized on postpartum days (PPD) 1, 7, 14 or 28 (n = 4 or 5 ewes/day). Ewes were checked twice daily for signs of labor or parturition. At hysterectomy, the residual placentomal or caruncular and intercaruncular areas of the uterine wall were dissected from the uteri of ewes on PPDs 1, 7 or 14, and sections (~1 cm) were fixed in 4% (w/v) paraformaldehyde. On PPD 28, sections from the mid-portion of each uterine horn were fixed in 4% (w/v) paraformaldehyde.
After 24 h, fixed tissues from all studies were dehydrated through a graded series of ethanol solutions and embedded in Paraplast Plus (Oxford Labware, St Louis, MO, USA) for histological analyses.
Western-blot analyses
Uterine flushes from study 1 were concentrated using Centricon-3 columns (Amicon, Beverly, MA, USA). Protein content of concentrated flushes (study 1) and fetal fluids (study 2) was determined using a Bradford protein assay (Bio-Rad, Hercules, CA, USA) with BSA as the standard. For study 1, uterine flush proteins (20 µg) were separated by non-denaturing/non-reducing 12% PAGE. For study 2, allantoic and amniotic fluid proteins (20 µg) were denatured and separated by 15% SDS/PAGE. Western-blot analyses of separated protein was conducted as described previously (Spencer et al. 1999a) using enhanced chemiluminescence detection. Immunoreactive galectin-15 was detected using primary rabbit anti-ovine galectin-15 serum (provided kindly by Dr Els N T Meeusen, Monash University, Melbourne, Australia; Dunphy et al. 2000) at a 1:2500 dilution. Negative control blots were performed in which primary antibody was replaced by rabbit serum at the same concentration.
Transmission electron microscopy (TEM)
Endometrium and conceptuses from day 16 of gestation (study 1) were fixed in a solution of 2% paraformaldehyde/ 3% glutar-aldehyde in 0.08M sodium cacodylate (pH 7.2). After fixation, tissues were dehydrated in a gradient of 10–100% ethanol and embedded in Unicryl resin (SPI Supplies, West Chester, PA, USA). Routine staining of semi-thick sections with 0.1% Toluidine Blue and 1% sodium borate (Borax; Na2B4O7·10H2O) was utilized to isolate areas of interest. Trimmed materials were then sectioned using an LKB ultramicrotome (type 4802A). The 70–90 nm-thick sections were stained with 10% uranyl acetate in 30% ethanol for 30 min followed by Reynolds’ lead citrate for 10 min (Reynolds 1963). Sections were examined and photographed using a Zeiss 10CA transmission microscope at 80 kV on Kodak electron microscope film 4489.
Immunogold TEM
Endometrium and conceptuses from day 16 of gestation (study 1) were fixed in 3% paraformaldehyde and 0.2% glutaraldehyde in 0.1M cacodylate buffer (pH 7.2) containing 5% (w/v) sucrose, dehydrated through ethanol, and embedded in Unicryl resin. Ultrathin sections were picked up on 300-hex nickel grids and floated on 10% heat-inactivated normal goat serum in 0.1% BSA/Tris for 30 min. Grids were transferred to drops of rabbit anti-ovine galectin-15 serum (1:2000) or rabbit serum for 1 h at room temperature. After washing three times with 50mM Tris (pH 7.4) in 0.1% BSA for 1 min each, five times in 50mM Tris (pH 7.4) for 1 min each and twice in PBS for 5 min each, the grids were post-fixed in 2% glutaraldehyde in PBS for 5 min and rinsed with water. Grids were then dried at room temperature and stained lightly with uranyl acetate in 50% (v/v) alcohol. TEM images were photographed as described above.
RNA isolation and analyses
Total cellular RNA was isolated from frozen intercaruncular and caruncular endometria from study 2 and intercaruncular endometrium from study 3 using the Trizol reagent (Gibco-BRL, Grand Island, NY, USA). For each ewe, denatured total cellular RNA (20 µg) was analyzed by slot-blot hybridization using a radiolabeled antisense cRNA probe generated by in vitro transcription with [
-32P]UTP (Amersham Pharmacia Biotech, Piscataway, NJ, USA) as described previously (Gray et al. 2004). Plasmid templates containing cDNAs for ovine galectin-15 (Gray et al. 2004) and 18 S rRNA (pT718S; Ambion, Austin, TX) were used to produce radiolabeled cRNA probes as described previously (Choi et al. 2001). Hybridization signals were detected by exposing washed slot blots to a phosphorimager screen and visualized and quantified using a Typhoon 8600 Variable Mode Imager (Molecular Dynamics, Sunnyvale, CA, USA).
In situ hybridization
Galectin-15 mRNA was localized in uterine tissue sections by in situ hybridization as described previously (Spencer et al. 1999b). Deparaffinized, rehydrated and deproteinated uterine sections (5 µm) were hybridized with radiolabeled antisense or sense cRNAs generated from linearized ovine galectin-15 (Gray et al. 2004) plasmid templates using in vitro transcription with [-35S]UTP. Autoradiographs of slides were prepared using Kodak NTB-2 liquid photographic emulsion. Slides were stored at 4 °C for 1 week as judged from autoradiographs, developed in Kodak D-19 developer, lightly counterstained with Gill’s hematoxylin (StatLab, Lewisville, TX, USA), dehydrated through a graded series of alcohol to xylene, and coverslips affixed with Permount (Fisher Scientific, Atlanta, GA, USA
Immunofluorescence analyses
Proteins were localized in frozen intercaruncular and caruncular endometrial tissue sections (8–10µm) collected in study 2 by immunofluorescence staining as described previously (Johnson et al. 1999). Briefly, frozen tissues were sectioned (8 µm) with a Hacker-Bright OTF cryostat (Hacker Instruments, Fairfield, NJ, USA) and mounted on Superfrost/Plus microscope slides (Fisher Scientific, Pittsburgh, PA, USA). Frozen sections were fixed in –20 °C methanol for 10 min, permeabilized with 0.3% Tween-20 (v/v) in 0.02M PBS, and then blocked in antibody dilution buffer [two parts 0.02M PBS/1.0% BSA (w/v)/0.3% Tween-20 (w/v; pH 8.0) and one part glycerol] containing 5% normal goat serum (v/v) for 1 h at room temperature, and incubated overnight at 4 °C with the rabbit anti-ovine galectin-15 antibody (1:1000) or rabbit serum (1:1000). Immunoreactive protein was then detected using a fluorescein-conjugated secondary antibody for 1 h at room temperature. Slides were overlaid with Prolong antifade mounting reagent and then coverslips added (Molecular Probes, Eugene, OR, USA).
Photomicroscopy
Photomicrographs of in situ hybridization slides were taken using a Nikon Eclipse E1000 photomicroscope (Nikon Instruments, Melville, NY, USA). Digital images were captured using a Nikon DXM 1200 digital camera and assembled using Adobe Photoshop 7.0 (Adobe Systems, Seattle, WA, USA). For immunoflourescence analyses, representative fluorescence images were recorded using a Ziess Axioplan microscope (Carl Zeiss, Thornwood, NY, USA) equipped with a Hamamatsu chilled 3CCD color camera (Hamamatsu Photonics, Bridgewater, NJ, USA) using Adobe Photoshop 7.0 image-capture software. TEM negatives were converted to digital images using an Epson Perfection 3200 photo scanner (Epson America, Long Beach, CA, USA) and assembled using Adobe Photoshop 7.0.
Statistical analyses
All quantitative data were subjected to least-squares analysis of variance using the General Linear Models procedures of the Statistical Analysis System (Cary, NC, USA). Analyses of steady-state levels of endometrial mRNA determined by slot-blot hybridization included the 18 S rRNA as a covariate to correct for differences in sample loading. Least-squares regression analyses were used to determine effects of gestational or postpartum day on endometrial galectin-15 mRNA levels. In all analyses, error terms used in tests of significance were identified according to the expectation of the mean squares for error. Data are presented as least-squares means with overall S.E. values.
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). Although the predicted size of galectin-15 from the inferred amino acid sequence was only 15.5 kDa (Gray et al. 2004), immunoreactive galectin-15 forms of ~60 and 80 kDa were observed in the uterine flush of day 14 and 16 cyclic ewes and day 14 pregnant ewes. Interestingly, immunoreactive galectin-15 forms of ~60, 80 and 100 kDa were observed in the uterine flush of day 16 pregnant ewes. Multimeric forms of galectin-15 protein were only minimally present, or were absent, in the uterine flush of day 12 cyclic or pregnant ewes.
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) and conceptus trophectoderm (Fig. 2) from day 16 pregnant ewes. These crystal structures were localized in the cytoplasm near the nucleus in the LE cells and were more abundant in the conceptus trophectodermal cells. The crystals appeared to be rhomboidal and were surrounded by a membrane. Immunogold labeling localized galectin-15 protein primarily to the crystalline inclusion bodies in both endometrial LE and conceptus trophectoderm.
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). Galectin-15 mRNA expression in the intercaruncular endometrium was lowest during early pregnancy from days 16 to 40, increased 3.5-fold between days 40 and 60 of pregnancy, and remained elevated to day 120 (quadratic effect of day, P < 0.001).
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). Between days 20 and 40 of pregnancy, galectin-15 mRNA was detected only in the sGE of the endometrium, because the LE was absent. During ovine placentation, the LE fuses with the trophoblast giant binucleate cells (BNCs) to form a syncytia beginning on day 16 when the BNCs differentiate (Wimsatt 1951, Wooding 1984). The LE reappears in the intercaruncular endometrial areas between days 40 and 60. On day 60 and thereafter, galectin-15 mRNA was detected in both the LE and sGE of the intercaruncular endometrium. Galectin-15 mRNA was not detected in the caruncular or cotyledonary areas of the placentomes (data not shown).
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). On day 40 of pregnancy, galectin-15 was observed at the apical surface of the sGE. By day 60, galectin-15 protein was observed on the LE as well as within the overlying trophectoderm of the chorion. This spatial pattern of expression was consistent throughout the latter portion of pregnancy. Galectin-15 protein was undetectable in the caruncular or cotyledonary areas of the placentomes (data not shown).
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). Galectin-15 protein was not detectable in amniotic fluid on any day of gestation (data not shown).
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). In study 3, galectin-15 mRNA was localized primarily to the LE during the postpartum period, with low expression also detected in the sGE (Fig. 7). On PPD 1, galectin-15 mRNA expression was variable, ranging from high to moderate or low abundance depending on the ewe. The pattern of galectin-15 expression in the LE was variegated, particularly on PPDs 1 and 7. Expression of galectin-15 mRNA was still detected in some areas of the LE on PPD 28.
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Discussion |
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stimulated galectin-15 gene expression in the endometrium. In the present study, analysis of galectin-15 in uterine flushes indicated that secreted extracellular galectin-15 is in a multimeric form, particularly as the amount of galectin-15 mRNA increases in the endometrial LE and sGE and galectin-15 protein increases in the uterine lumen on days 14 and 16 of pregnancy (Gray et al. 2004). Other galectin family members are known to homodimerize and form multimers (Cho & Cummings 1996, Yang et al. 1998, Dunphy et al. 2002). The effects of galectin multimerization on biological function are not well understood, particularly in regard to ability of galectins to bind to glycoproteins and/or glycolipid receptors and initiate biological responses. Immunogold electron microscopy revealed that within the endometrial LE and conceptus trophectoderm, galectin-15 protein was localized to large, membrane-bound rhomboidal crystal structures. The working hypothesis is that galectin-15 protein forms crystals within the endometrial LE and is also secreted into the uterine lumen as a part of histotroph. The conceptus trophectoderm then absorbs extracellular galectin-15 in the uterine histotroph, wherein it becomes a component of intracellular crystals as originally described for the 14 kDa protein, e.g. galectin-15, by Kazemi and coworkers (Kazemi et al. 1990). In the ovine conceptus trophectoderm, crystals were found to increase in number and size between days 10 and 18 of pregnancy (Wintenberger-Torres & Flechon 1974). The presence of crystals in sheep uterine histotroph (or uterine milk), present between maternal and fetal intercotyledonary membranes, is well documented (Wimsatt 1951, Hoffman & Olson 1984). Progesterone-induced crystal structures in the endometrium and/or conceptus trophectoderm have been described in the sheep (Wintenberger-Torres & Flechon 1974, Hoffman & Olson 1984, Kazemi et al. 1990), mouse (Calarco & Szollosi 1973), rabbit (Nakoa et al. 1971, Daniel & Kennedy 1978) and human (Nakoa et al. 1971). Although the biological role(s) of galectin-15 crystals in the uterine epithelia is not known, the intracellular role of other galectins include modulation of cell growth, differentiation and apoptosis through functioning as pre-mRNA splicing factors and interacting with specific intracellular ligands such as Ras and Bcl-2 (Hernandez & Baum 2002, Liu et al. 2002).
During synepitheliochorial placentation in sheep, trophoblast giant BNCs begin to differentiate between days 14 and 16 and then fuse apically with the endometrial LE and form syncytia, thereby assimilating and replacing the endometrial LE (Wimsatt 1951, Wooding 1984). In the intercaruncular endometrium, the LE reappears between days 40 and 60 of pregnancy, and this was associated with an increase in galectin-15 mRNA in the intercaruncular endometrium in the present study. Galectin-15 mRNA and protein expression was not observed in the placentomes, which are comprised of placental cotyledons and endometrial caruncles devoid of LE. Although the placenta is expelled shortly after parturition, regrowth of the entire LE covering the endometrial caruncules takes at least 4 weeks during postpartum involution of the uterus (Gray et al. 2003). The expression of galectin-15 mRNA in the epithelia is variegated during the postpartum period and steady-state levels declined slowly over the month following parturition. This unique expression pattern suggests that the phenotype of the endometrial epithelia is changing rapidly during uterine involution.
Although galectin-15 mRNA was found exclusively in the endometrial LE and sGE of the uterus, immunoreactive galectin-15 protein was detected predominantly in the chorion/trophectoderm of the placenta as well as in the allantoic fluid. Galectin-15 protein is present in the uterine lumen of early pregnant ewes as well as in uterine milk recovered from the non-gravid horn of unilaterally pregnant ewes (Gray et al. 2004). Other galectin family members also exhibit dual localization, being found in both extracellular (cell-surface and medium) and intracellular (cytoplasm and, in some cases, the nucleus) compartments (Hughes 1997). Although galectins are often present on cell surfaces or in the extracellular matrix, galectins lack a classical secretion signal sequence and are secreted by a novel apocrine mechanism that does not involve the endoplasmic reticulum–Golgi pathway (Hughes 1999, Boulianne et al. 2000). Similarly, ovine galectin-15 lacks a signal peptide (Dunphy et al. 2000, Gray et al. 2004). After implantation, the chorioallantois develops unique structures, termed areloae, that develop over the mouth of each uterine gland as specialized areas for absorption and transport of uterine histotroph into the conceptus (Bazer 1975). These results support the idea that galectin-15 protein is synthesized by the endometrial LE and sGE and then secreted into the uterine lumen, where it is absorbed by the placenta, transported into the fetal circulation, and cleared by the kidney into the allantois via the urachus (Bazer 1975, Roberts & Bazer 1988). Although the allantois was initially considered a reservoir for waste products of the fetus, it serves to store most secreted proteins from the endometrium (Bazer et al. 1975, Moffatt et al. 1987). In contrast, amniotic fluid is not in the path for protein clearance by the fetal kidney and, therefore, does not function in this capacity. In the present study, galectin-15 protein was not detected in amniotic fluid, but was present in allantoic fluid where it may simply serve as a source of amino acids for fetal and placental growth and function or possess other biological functions. During human pregnancy, galectin-13 (or placental protein-13) plays a role in calcium-mediated depolarization, liberation of arachidonic acid and the formation of thromboxane in the placenta (Burger et al. 2004). Indeed, a reduction in galectin-13 is associated with intrauterine growth retardation (Burger et al. 2004).
Another potential biological function of endometrial galectin-15 throughout pregnancy and during involution may be to modulate inflammatory and immune responses. Under the influence of progesterone, uterine lymphocyte dynamics and functions are altered that inhibit maternal responses to the fetal–placental semi-allograft which is critical for pregnancy success (Clark et al. 1999). As in other mammals, the ovine uterus has pregnancy-associated changes in lymphocytes, macrophages and natural killer cells which are differentially regulated by conceptus and maternal factors (Gogolin-Ewens et al. 1989, Lee et al. 1992, Fox et al. 1998, Tekin & Hansen 2002, 2004). Evidence suggests that progesterone stimulates the endometrium to induce synthesis of regulatory molecules that affect lymphocyte dynamics (Majewski et al. 2001). A progesterone-stimulated immunoregulatory protein family is the uterine serpins or uterine milk proteins (Leslie & Hansen 1991, Hansen 1998). Similarly, galectin-15 is also induced by progesterone and a component of uterine milk (Gray et al. 2004). Interestingly, galectin-15 was originally found to be induced in gastrointestinal tissue and secreted into the intestinal lumen in response to inflammation and eosinophil infiltration after infection of sheep with the helminth, Haemonchus contortus (Dunphy et al. 2000). Given that several other galectins regulate innate and adaptive immune responses (Rabinovich et al. 2002, Young & Meeusen 2004), one may speculate that galectin-15 in the ovine endometrium is another progesterone-induced immunoregulatory factor that modulates the maternal intrauterine immune system, thereby protecting the conceptus and promoting placental growth, which is a process strikingly similar to host–parasite interactions (Guimond et al. 1999). Future experiments will assess the intracellular and extracellular role(s) of galectin-15 in regulation of uterine immune responses, placental morphogenesis and function, and fetal growth.
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References |
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