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Endocrinology Vol. 138, No. 12 5511-5517
Copyright © 1997 by The Endocrine Society

ARTICLES

Identification and Characterization of a Mouse Homolog for Decidual/Trophoblast Prolactin-Related Protein1

Kyle E. Orwig2, Ryuta Ishimura3, Heiner Müller4, Bing Liu and Michael J. Soares

Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160

Address all correspondence and requests for reprints to: Dr. Michael J. Soares, Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas 66160-7401. E-mail: msoares{at}kumc.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Decidual/trophoblast PRL-related protein (d/tPRP) is one member of a large placental PRL gene family composed of at least nine members in the rat and four in the mouse. Only placental lactogen I and II have been characterized in both rat and mouse. The identification of mouse homologs for rat placental PRL family members will facilitate gene manipulation studies aimed at identifying functions for these hormones. In this report, we establish the presence of d/tPRP in the mouse and characterize its complementary DNA, protein, and pattern of expression during mouse gestation. Evaluation of the National Center for Biotechnology Information database of expressed sequence tags resulted in the identification of several mouse complementary DNA clones exhibiting significant homology to rat d/tPRP. One of these clones was obtained from IMAGE Consortium and Research Genetics for further investigation. The full-length mouse clone was found to have an 81% nucleotide homology with rat d/tPRP and to encode a 239-amino acid protein. Like rat d/tPRP, the mouse protein contains two putative N-linked glycosylation sites and six homologously located cysteine residues. Mouse d/tPRP maps to chromosome 13 along with other members of the mouse PRL family. Like the rat, mouse d/tPRP messenger RNA and protein are expressed by antimesometrial decidual cells and spongiotrophoblast and trophoblast giant cells in the junctional zone of the placenta. In summary, we have established the presence of d/tPRP in the mouse and demonstrated its similarity in structure and pattern of expression to rat d/tPRP. This level of conservation between species expands the biological significance of d/tPRP during pregnancy and provides additional opportunities for evaluating its function.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
DECIDUAL/TROPHOBLAST PRL-related protein (d/tPRP) is one member of a large protein family structurally related to PRL (1). To date, at least nine members of the PRL family have been identified in the rat placenta, including placental lactogens (PL-I, PL-Iv, and PL-II), PRL-like proteins (PLP-A, PLP-B, PLP-C, PLP-Cv, and PLP-D), and PRL-related proteins (d/tPRP). With the exception of PL-I and PL-II, homologous members of the rat placental PRL family have not been identified in the mouse (reviewed in Ref.2).

Members of the placental PRL family can be divided into two groups based on their biological activity (reviewed in Ref.2). Classical PRL family members, including PL-I, PL-Iv, and PL-II, bind the PRL receptor and stimulate PRL-like bioactivity. Nonclassical PRL family members possess distinct biological activities. Progress in identifying the functions of nonclassical PRL family members has been limited to two mouse members. Proliferin (PLF) stimulates uterine cell proliferation (3) and blood vessel development (4). In contrast, PLF-related protein (PLF-RP) opposes blood vessel development (4).

Although the structure and patterns of expression of d/tPRP in rat uteroplacental tissues have been reported (1, 5, 6, 7), the biological role of d/tPRP during pregnancy has yet to be fully resolved. Approaches for investigating the physiology of d/tPRP and other nonclassical PRL family members would be significantly advanced by the availability of a mouse model and the application of gene manipulation strategies.

Evidence for a mouse d/tPRP came originally from Northern blot analysis of mouse decidual RNA using a rat d/tPRP complementary DNA (cDNA) probe (Orwig, K. E., and M. J. Soares, unpublished results). Further evidence for a mouse d/tPRP was derived from inspection of the National Center for Biotechnology Information (Bethesda, MD) database of expressed sequence tags (dbEST) containing information on expressed sequence tags from several mouse conceptus cDNA libraries (8). In this report, we establish the presence of d/tPRP in the mouse, characterize its cDNA, and describe its expression pattern during pregnancy.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Reagents
FBS and donor horse serum were purchased from JRH Bioscience (Lenexa, KS). Reagents for PAGE were purchased from Bio-Rad (Hercules, CA). All restriction enzymes, polymerases, and DNA ligase were purchased from New England Biolabs (Beverly, MA). Mouse d/tPRP cDNA was obtained from Research Genetics (Huntsville, AL). The 293 cell line of human fetal kidney origin and the pSV2neo vector were obtained from American Type Culture Collection (Rockville, MD). DNA extraction kits were purchased from Qiagen (Chatsworth, CA). Nitrocellulose and nylon membranes were obtained from Schleicher and Schuell (Keene, NH). T7 DNA sequencing kits were acquired from U.S. Biochemical (Cleveland, OH). Radiolabeled nucleotides were purchased from DuPont-New England Nuclear (Boston, MA). Prime-It random primer labeling kits were obtained from Stratagene (La Jolla, CA). TRIzol reagent for RNA extraction and the pCMV-SPORT2 expression vector were obtained from Life Technologies (Gaithersburg, MD). Avidin-biotin immunoperoxidase kits were purchased from Zymed Laboratories (South San Francisco, CA). Reagents for the detection of immune complexes by enhanced chemiluminescence were obtained from Amersham Corp. (Arlington Heights, IL). Unless otherwise noted, all chemicals and reagents were purchased from Sigma Chemical Co. (St. Louis, MO).

Animals and tissue preparation
CD-1 mice were obtained from Charles River Laboratories (Wilmington, MA). Holtzman rats were acquired from Harlan Sprague-Dawley (Indianapolis, IN). The animals were housed in an environmentally controlled facility, with lights on from 0600–2000 h, and allowed free access to food and water. Timed pregnancies and tissue dissections were performed as previously described (9, 10). The presence of a copulatory plug was designated day 1 of pregnancy. Pseudopregnancy was induced by mating with vasectomized males. Deciduomal reactions were induced on day 4 of pseudopregnancy by injection of 50–75 µl sesame oil/uterine horn. Protocols for the care and use of animals were approved by the University of Kansas animal care and use committee.

Generation of recombinant mouse and rat d/tPRP
The 293 human fetal kidney cell line was used as a host for the expression of recombinant mouse d/tPRP. 293 cells were routinely maintained in MEM supplemented with 20 mM HEPES, 100 U/ml penicillin, 100 µg/ml streptomycin, and 10% FBS with an atmosphere of 5% CO2-95% air in a 37 C humidified incubator. Mouse d/tPRP cDNA in the pCMV-SPORT2 expression vector was cotransfected with pSV2 neo (a plasmid providing neomycin resistance) into 293 cells via electroporation. Cells were selected for 2 weeks in the presence of geneticin (G418; 500 µg/ml) as previously described (11, 12). Cells were grown to confluence and transferred to serum-free culture medium. Conditioned medium was collected after 72 h, clarified by centrifugation, and stored at -20 C until use. Recombinant rat d/tPRP was generated as previously described (12).

Characterization of d/tPRP cDNA
Examination of the dbEST from day 8.5 mouse embryo revealed the presence of several cDNA clones exhibiting a high degree of homology with rat d/tPRP. We obtained one of these clones (EST name: mp06g07.rl; GenBank accession no. AA108035) from IMAGE Consortium and Research Genetics (8). The cDNA clone was inserted into the SalI and NotI sites of the pCMV-SPORT2 vector. DNA sequencing was performed by the dideoxy chain termination method using Sequenase and [35S]deoxy-ATP (13). Both strands of the mouse d/tPRP cDNA were completely sequenced using primers for T7 and SP6 flanking regions as well as internal oligonucleotides. Reaction products were resolved on 6% polyacrylamide urea gels, dried, and exposed to Kodak XAR film (Eastman Kodak, Rochester, NY).

Chromosomal assignment
Chromosomal localization of the mouse d/tPRP gene was determined using the Jackson Laboratory interspecific backcross panel (14). Initially, genomic DNA was obtained from C57BL/6JEi and SPRET/Ei mice for the purpose of identifying polymorphisms between the two strains. Based on sequence analysis of the mouse d/tPRP cDNA (present study) and alignment with the rat d/tPRP gene (6), primers were designed to amplify each intron and the 3'-flanking sequence of mouse d/tPRP by PCR. A distinct polymorphism was identified within the putative intron C of mouse d/tPRP. Amplification of intron C from the C57BL/6JEi strain and subsequent digestion with the NlaIV restriction enzyme resulted in the generation of two fragments, 840 and 80 bp in size. Similar analysis of the SPRET/Ei strain resulted in the generation of a single 920-bp fragment due to the absence of the NlaIV restriction site. This polymorphism was used to determine the chromosomal localization of mouse Dtprp using the Jackson Laboratory 94 animal interspecific backcross panel (C57BL/6JEi x SPRET/Ei)F1 x SPRET/Ei, known as Jackson BSS (14).

Analysis of d/tPRP expression
Northern blot analysis. Northern blots were performed as previously described by our laboratory (6, 15). RNA was extracted from tissues essentially as described by Chomczynski and Sacchi (16), using TRIzol. Total RNA (15 µg) was separated on a 1% agarose gel and transferred to a nylon membrane. Blots were probed with 32P-labeled mouse d/tPRP cDNA. The ribosomal protein L7 (rpL7) control probe was generated by PCR (17). Specific oligonucleotide primers amplified a 246-bp rpL7 fragment that was random primer labeled using Klenow and [32P]deoxy-ATP.

In situ hybridization. d/tPRP messenger RNA (mRNA) was detected in frozen tissue sections as previously described (7, 15). The full-length mouse d/tPRP cDNA was linearized and used as a template for the synthesis of 35S-labeled sense and antisense RNA probes.

Western blot analysis. Western blot analysis for d/tPRP was performed as previously described (12). Samples were separated by electrophoresis in 12% polyacrylamide gels under reducing conditions and transferred to nitrocellulose membranes. Immunoreactive bands were visualized using a chemiluminescent detection system. Native and recombinant preparations of rat d/tPRP (12) were used as positive controls in the immunoblotting experiments.

Immunocytochemistry. Tissue and cellular localization of d/tPRP was determined by immunocytochemistry using a streptavidin-biotin immunoperoxidase kit for rabbit IgG (7). The immunostained sections were counterstained with hematoxylin. The specificity of the immunoreactions was demonstrated using preimmune serum.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
d/tPRP cDNA characterization
Evidence for the expression of a d/tPRP-like transcript in the pregnant mouse uterus arose from Northern blot analyses using rat d/tPRP cDNA as a probe (data not shown). This result prompted us to examine the National Center for Biotechnology Information dbEST to search for possible mouse homologs of rat d/tPRP. Results from the database search indicated that several cDNA clones have been deposited in the dbEST that share significant homology with rat d/tPRP. These clones were derived from cDNA libraries from day 8.5 mouse embryos, day 10.5 mouse embryos, and day 13.5–14.5 mouse placenta as part of the IMAGE Consortium (8).

We have characterized one representative of mouse d/tPRP-like cDNA clones (mp06g07.rl) in the present study (GenBank accession no. AF015729). The mouse cDNA was 81% identical to rat d/tPRP at the nucleotide level and encodes a 239-amino acid protein. Like rat d/tPRP, the predicted amino acid sequence of the mouse protein contains two putative N-linked glycosylation sites and six homologously located cysteine residues (1). Based on homology with rat d/tPRP, it was determined that the mouse protein contains a 28-amino acid signal peptide (1). A polyadenylation signal is located 113 nucleotides downstream of the stop codon (TAA). Amino acid comparisons with members of the rat PLP-C subfamily (d/tPRP, PLP-D, PLP-C, and PLP-Cv) are shown in Fig. 1Go (sequences were aligned using the ClustalW multiple sequence alignment program). The predicted amino acid sequence for mouse d/tPRP shares 66% identity and 84% similarity with rat d/tPRP (Table 1Go). Mouse d/tPRP showed progressively less amino acid similarity with the other members of the PLP-C subfamily (Fig. 1Go and Table 1Go). Boxes and Roman numerals in Fig. 1Go indicate several regions of interest. Regions I (amino acids 12–30), IV (amino acids 149–161), and VI (amino acids 205–216) appear to be conserved in all PRL family members. Regions II (amino acids 69–81) and V (amino acids 169–178) are unique to members of the rat PLP-C subfamily (Fig. 1Go) and mouse PLF-RP (18). Recent characterization of the rat d/tPRP and rPLP-Cv genes demonstrated that region II is encoded by a unique exon (exon 3) relative to the prototypical PRL gene structure (6, 19). Although the gene structures for mouse d/tPRP, rPLP-D, rPLP-C, and PLF-RP have not yet been characterized, it is likely that they also contain an additional exon. Region II may contribute to the structure and/or function of PLP-C subfamily members. Finally, regions III (amino acids 109–118) and VII (amino acids 220–233) seem to be unique to mouse and rat d/tPRP. The locations of these regions coincide with the locations of regions of human PRL that are essential for PRL receptor binding and bioactivity (20). All amino acid numbering is for mouse d/tPRP.



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  		Figure 1. Amino acid homology between mouse d/tPRP and rat PLP-C subfamily proteins. Amino acid sequences of mouse d/tPRP (present study), rat d/tPRP (1), rat PLP-D (27), rat PLP-C (19, 28), and rat PLP-Cv (19) are listed by one-letter designations. Sequences were aligned using the ClustalW multiple sequence alignment program. Shaded areas denote identity with mouse d/tPRP. Seven regions of interest have been boxed and labeled with Roman numerals (see Results).

 

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  		Table 1. Sequence comparison between mouse d/tPRP and other members of the rodent PRL family

 
Chromosomal localization
The chromosomal location of the mouse d/tPRP gene (Dtprp) was determined using the Jackson BSS cross (14). The allele pattern of Dtprp was compared with the 2700 other loci previously mapped in the Jackson BSS cross, and linkage was found to the proximal end of chromosome 13. Dtprp cosegregates with mouse placental lactogen-I (Pl1) and is located approximately 6 centimorgans distal (relative to the centromere) to proliferin (Plf). The arrangement of these PRL-related genes relative to other chromosome 13 loci is as follows: centromere-D13Abb1e-Plf-D13Bir7-D13Mit3-D13Hun2-Dtprp, Pl1-Agtr1a.

d/tPRP expression patterns
The tissue distribution of mouse d/tPRP mRNA was determined by Northern blot analysis (Fig. 2Go). d/tPRP expression was observed in day 8 deciduoma and placentas from days 13, 16, and 19 of pregnancy. d/tPRP transcripts were not detected in mouse brain, thymus, heart, lung, diaphragm, liver, spleen, kidney, or ovary. This pattern of expression is identical to that of rat d/tPRP (6, 7). The integrity of the RNA was verified by hybridization with the rpL7 probe.



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  		Figure 2. Tissue-specific expression of mouse d/tPRP. Total RNA was collected from day 8 deciduoma tissue and day 13, day 16, and day 19 placenta, brain, thymus, heart, lung, diaphragm, liver, spleen, kidney, and ovary. The distribution of d/tPRP mRNA in mouse tissues was determined by Northern blot analysis. d/tPRP expression was restricted to deciduomal and placental tissues, similar to the pattern previously reported in the rat (6). The control probe for rpL7 was used to demonstrate equal loading and integrity of the RNA.

 
Production of the d/tPRP protein in mouse uteroplacental tissues was confirmed by Western blot analysis using polyclonal antibodies to rat d/tPRP (12). Figure 3Go (top panel) demonstrates the ability of rat d/tPRP antibodies to cross-react with recombinant mouse d/tPRP. d/tPRP-immunoreactive bands were observed in the deciduum and placenta of both rat and mouse (Fig. 3Go, bottom panel). Please note that the recombinant mouse d/tPRP comigrated with the 29-kDa rat d/tPRP.



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  		Figure 3. Western blot analysis for d/tPRP. The presence of the d/tPRP protein in mouse tissues was confirmed by Western blot analysis using polyclonal antibodies to rat d/tPRP (1:1000 dilution). Top panel, Polyclonal antibodies to rat d/tPRP recognized the 29-kDa recombinant rat d/tPRP (lane A) as well as native d/tPRP from rat decidua (lane B) and rat placenta (lane C). Lane D demonstrates the ability of the rat d/tPRP antibodies to cross-react with recombinant mouse d/tPRP. Bottom panel, A 29-kDa d/tPRP-immunoreactive band was detected in rat decidua (lane E), rat placenta (lane F), mouse decidua (lane G), and mouse placenta (lane H).

 
In situ hybridization and immunocytochemistry were used to determine the cellular localization of d/tPRP in mouse uteroplacental tissues. In situ hybridization results (Fig. 4Go: A, darkfield; B, brightfield) demonstrated that within the day 8 conceptus, d/tPRP expression was localized primarily to the antimesometrial decidua. Results from immunocytochemical studies demonstrated that mouse d/tPRP protein was expressed in the antimesometrial decidua of the day 9 conceptus (Fig. 4CGo). d/tPRP immunoreactivity was also observed in trophoblast giant and spongiotrophoblast cells in the junctional zone of chorioallantoic placentas from days 13 and 16 of gestation (Fig. 4Go, D–G). This expression pattern is consistent with previous reports for rat d/tPRP (7).



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  		Figure 4. Localization of d/tPRP expression in developing uteroplacental structures. d/tPRP mRNA and protein localization in uteroplacental tissues was determined by in situ hybridization and immunocytochemistry. For in situ hybridization, sections were hybridized with 35S-labeled d/tPRP sense or antisense riboprobe. A, Darkfield micrograph demonstrating positive antisense d/tPRP hybridization is restricted to antimesometrial decidua in the cross-section through a day 8 mouse conceptus (magnification, x20). B, Brightfield micrograph of the same day 8 mouse conceptus section (magnification, x20). No hybridization signal was detected using the d/tPRP sense probe (data not shown). For immunocytochemistry, transverse sections of mouse uteri at conceptus sites and placentas were stained for the presence of d/tPRP (C–G) using polyclonal antibodies to d/tPRP and a streptavidin-biotin immunoperoxidase kit. The antiserum was used at a final dilution of 1:250. C, Day 9 conceptus (magnification, x20). Please note that specific immunostaining was localized predominantly to the antimesometrial deciduum. D, Day 13 placenta (magnification, x10); E, day 16 placenta (magnification, x10); F, day 13 placenta (magnification, x500); G, day 16 placenta (magnification, x500). Please note that d/tPRP immunoreactivity was specifically localized to trophoblast giant cells (TGC) and spongiotrophoblast cells within the junctional zone of the placenta. No signal was detected using preimmune serum, demonstrating the specificity of the antibody (data not shown). md, Mesometrial decidua; amd, antimesometrial decidua; troph, trophoblast; jz, junctional zone; lz, labyrinth zone; tgc, trophoblast giant cell; sptc, spongiotrophoblast cell; gc, glycogen cell.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
d/tPRP is one member of a large rodent placental PRL family comprised of at least nine members in the rat and four members in the mouse (2). To date, only two of these members, PL-I and PL-II, have been characterized in both rat and mouse. In this report we have identified and characterized a mouse homolog of rat d/tPRP. Mouse d/tPRP is similar to its rat counterpart in sequence, tissue distribution, and temporal expression. In both species, d/tPRP is expressed in antimesometrial decidual cells. d/tPRP expression appears in spongiotrophoblast and trophoblast giant cells of the placenta during midpregnancy and persists until parturition (present study and Refs. 6 and 7). These results are significant for two reasons: 1) the high degree of d/tPRP conservation between species implies physiological relevance during pregnancy; and 2) approaches for investigating the physiology of d/tPRP will be significantly advanced by the availability of a mouse model and the application of gene manipulation strategies.

Comparisons between mouse and rat d/tPRP and other members of the PLP-C subfamily were useful in identifying regions that are unique to d/tPRP, regions that are shared between all members of the PLP-C subfamily, and regions that are characteristic of all PRL family members. Inclusion of mouse d/tPRP in the PLP-C subfamily is supported by its sequence homology with rat d/tPRP and the presence of region II that is characteristic of PLP-C subfamily members as well as PLF-RP (reviewed in Ref.2). In the genes for rat d/tPRP and PLP-Cv, region II is encoded by an extra exon located between exons 2–3 of the prototypical PRL gene structure (6, 19). Although the gene structures for mouse d/tPRP and the other PLP-C subfamily members have not been characterized, it is likely that they also contain an additional exon.

Mouse and rat d/tPRP contain two regions of homology (regions III and VII) that are distinct from all other members of the PLP-C subfamily. It is possible that these regions contribute to a distinct mode of action for d/tPRP. Interestingly, the locations of these regions coincide exactly with the locations of regions of human, mouse, and rat PRL and PLs that are important for PRL receptor binding and bioactivity (20). The tertiary structure of the PRL protein brings helix 1 from the N-terminus, and loop 1 (connecting helixes 1 and 2) and helix 4 from the C-terminus into close proximity to form receptor-binding site 1 (20). Key PRL receptor binding determinants in these regions have not been conserved in d/tPRP (see Ref. 20 for a review), thus explaining its inability to stimulate the PRL signaling cascade (12). It is possible that d/tPRP has retained the PRL protein scaffolding to generate a receptor-binding site, but has unique amino acid determinants that direct binding to its cognate receptor. There is limited sequence homology between members of the PLP-C subfamily in these regions, suggesting that each member may have unique binding determinants and possibly a unique receptor.

The identity of a specific receptor for d/tPRP has yet to be determined. It is not known whether d/tPRP coevolved with its own specific receptor, uses a preexisting receptor and signaling cascade, or acts through some novel signaling system. PLF is known to exert its effects on endothelial cells through the mannose 6-phosphate/insulin-like growth factor II receptor (21, 22, 23). We have previously reported that rat d/tPRP associates with heparin-containing molecules and is localized at least in part in the decidual extracellular matrix. Therefore, d/tPRP is ideally situated to influence the behavior of decidual cells and cells traversing the decidua, including trophoblast, endothelial, and immune cells (7). Whether mouse d/tPRP is similarly distributed within the decidual extracellular matrix remains to be determined.

The Dtprp gene maps to mouse chromosome 13 along with other members of the mouse PRL family (24). The accumulation of data regarding the clustering of PRL family members on the same chromosome supports the hypothesis that individual members arose from duplication and divergent evolution from a common ancestral gene (25, 26). Colocalization of PRL family genes may also allow for common or coordinated regulation of expression. The observations that no recombination events occurred between the Dtprp and Pl1 loci on mouse chromosome 13 in the Jackson BSS cross suggests that these genes are closely linked. In contrast, the Plf locus is separated from Dtprp and Pl1 by several intervening genes and several cross-over events. The significance of this physical separation is not known.

The tissue-specific and temporal expression pattern of d/tPRP in the mouse closely parallels its counterpart in the rat. In both species, d/tPRP mRNA and protein are present at high levels from the time of implantation until parturition. The maintenance of d/tPRP expression throughout pregnancy requires a complex interplay between both maternal and fetal tissues. Collectively, these observations suggest potential physiological importance for d/tPRP during pregnancy. The availability of a mouse model creates new opportunities for studying d/tPRP physiology.


   Acknowledgments
 
We thank Lucy Rowe and Mary Barter of Jackson Laboratory for their assistance in determining the chromosomal location of d/tPRP. Lois Maltais of Jackson Laboratory assigned nomenclature and accessioned the Dtprp locus to the mouse genome database (MGD). We appreciate the guidance provided by Dr. S. K. Dey and Jue Wang for the in situ hybridization experiments. We thank Donna Millard for her advice regarding the in situ hybridization and immunocytochemistry experiments.


   Footnotes
 
1 This work was supported by grants from the NICHHD (HD-20676, HD-29797, and HD-33994). The sequence reported in this manuscript has been deposited in the GenBank database (accession no. AF015729). Chromosomal localization data for mouse Dtprp can be accessed in the Mouse Genomic Database (accession no. JNUM-42315). Back

2 Supported by a fellowship from the Lalor Foundation. Back

3 Present address: Laboratory of Cellular Biochemistry, University of Tokyo, Tokyo, Japan. Back

4 Supported by a fellowship from the Deutsche Forschungsgemeinschaft of Germany (Mu1183/1–1). Back

Received July 25, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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