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Endocrinology Vol. 140, No. 11 5095-5101
Copyright © 1999 by The Endocrine Society

ARTICLES

Prolactin (PRL)-Like Protein J, a Novel Member of the PRL/Growth Hormone Family, Is Exclusively Expressed in Maternal Decidua1

Daniel J. Toft and Daniel I. H. Linzer

Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, Illinois 60208

Address all correspondence and requests for reprints to: Dr. Daniel I. H. Linzer, Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, 2153 Sheridan Road, Evanston, Illinois 60208. E-mail: dlinzer{at}nwu.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
A search of a nonmouse, nonhuman, expressed sequence tag database for messenger RNAs in the PRL/GH family has identified a novel rat complementary DNA clone. The encoded protein, designated PRL-like protein J (PLP-J), is predicted to be synthesized as a precursor of 211 amino acids, modified by N-linked glycosylation, and secreted as a mature glycoprotein of 182 residues. PLP-J messenger RNA synthesis is limited to early pregnancy with abundant expression on day 7, slightly declining expression on day 9, and no detectable expression by day 11. Unlike most other PRL family members, PLP-J does not appear to be synthesized by placental trophoblasts but, rather, by decidual cells surrounding the implantation site. By sequence similarity to rat PLP-J, a murine clone was identified in a mouse expressed sequence tag database. Mouse PLP-J was used to map the gene to a 700-kb region of mouse chromosome 13 that includes other members of the PRL/GH family.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE RODENT placenta is the source of many hormones in the PRL/GH family (1, 2, 3, 4, 5, 6), including at least 15 distinct proteins expressed in either the rat or mouse (7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21). The receptors and biological functions of many of these hormones remain to be elucidated. Among the members with demonstrated bioactivity are the placental lactogens (PLs) that bind to the PRL receptor and elicit PRL-like bioactivities, such as the induction of progesterone production by the corpus luteum (22). In the mouse, the angiogenic and antiangiogenic proteins proliferin (PLF) and proliferin-related protein (PRP) are important modulators of blood vessel development during pregnancy (23). PLF accounts for the majority of proangiogenic activity secreted by midgestation placental cultures and is important for in vivo decidual neovascularization (24). Conversely, PRP is a potent antiangiogenic protein secreted from mid- to late gestation (23). It is speculated that PRP may limit endothelial invasiveness by creating a zone of predominantly antiangiogenic activity at the border between maternal and fetal tissue (1). PRL-like protein A (PLP-A) has recently been shown to bind to natural killer cells and to inhibit their cytolytic activity (25), whereas the murine proteins PLP-E and -F, which share 54% identity at the amino acid level, have been found to bind to splenic and bone marrow megakaryocytes and (at least for PLP-E) to stimulate megakaryocyte differentiation (26).

Many PRL family hormones with undefined receptors and functions, orphan hormones, can be grouped into what has been termed the PLP-C subfamily. Presently, this subfamily consists of PLP-C, -Cv, -C{alpha}, -D, -H, and d/tPRP. The defining characteristics of this subfamily are a high level of amino acid sequence identity and a six-exon/five-intron gene structure (5). With the exception of d/tPRP, an additional feature of this subfamily is synthesis from mid- to late pregnancy in both spongiotrophoblast and giant trophoblast cells (12, 13, 14, 15). In the rat, d/tPRP expression begins in the antimesometrial decidua as early as day 6 and is followed by expression in spongiotrophoblast and giant trophoblast cells from midgestation throughout the remainder of pregnancy (27). The murine homolog to d/tPRP is termed simply dPRP, reflecting the fact that only decidual expression has been observed (28).

The remaining known member of the PRL family is PLP-B. PLP-B synthesis occurs in both decidual and spongiotrophoblast cells, peaking on days 10 and 12, respectively (11). As with d/tPRP, the presence of this protein both before and after placentation suggests an important role in maintaining gestation. Additionally, the provocative midpregnancy switch from decidual to trophoblast expression coinciding with the regression of the maternal decidua and the development of the true chorioallantoic placenta suggests the coordinate regulation of the d/tPRP and PLP-B genes between the mother and the fetus.

Given the wide range of functions exhibited by the characterized members of the PRL family, the identification of other related hormones is expected to reveal additional regulatory functions essential for the physiological changes that occur during pregnancy. We report here the discovery of a novel PRL-related hormone and its initial characterization.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and animal care
Timed pregnant Sprague Dawley rats (Charles River Laboratories, Inc., Wilmington, MA) were maintained on days of 14 h of light and 10 h of darkness, with lights on at 0600 h. Food and water were freely available. All procedures were approved by the Northwestern University animal care and use committee.

Database screening and DNA sequence analysis
The nonmouse, nonhuman expressed sequence tag (EST) database available from the National Center for Biotechnology Information (accessed at http://www.ncbi.nlm.nih.gov/cgi-bin/BLAST/nph-newblast?Jform = 0) was searched for sequences similar to mouse PLF using BLAST. EST complementary DNA (cDNA) sequences similar to PLF were screened for identity to previously characterized family members found in the nonredundant database consisting of GenBank+EMBL+DDBJ+PDB sequences (but no EST, STS, GSS, or HTGS sequences) using BLAST. An EST cDNA that represented a novel rat PRL family messenger RNA (mRNA) was obtained from Genome Systems (St. Louis, MO). Plasmid DNAs were purified from bacterial lysates by alkaline lysis. The nucleotide sequence of PLP-J was determined using primers corresponding to both vector-specific and internal oligonucleotides. Sequencing was performed on an ABI 310 PRISM genetic analyzer using Big Dye fluorescent terminators (Perkin Elmer Corp., Foster City, CA). The major open reading frame and predicted translation product were identified using GeneWorks (Intelligenetics, Inc., Mountain View, CA).

RNA filter and in situ hybridization
Total RNA was prepared from pregnant rat tissues with Tri-Reagent (Sigma Chemical Co., St. Louis, MO) according to the manufacturer’s instructions. For filter hybridizations, 20 µg total RNA/lane were separated on 1% formaldehyde-agarose gels, transferred to nylon membranes (Schleicher & Schuell, Inc., Keene, NH), and exposed to UV light to cross-link the RNA to the membranes. Digoxigenin-labeled riboprobes were synthesized using either T7 or T3 RNA polymerase in a reaction of 20 µl containing 0.5 µg linearized template DNA, 1 x transcription buffer (Roche Molecular Biochemicals, Indianapolis, IN), 40 U ribonuclease inhibitor (Promega Corp., Madison, WI), 400 µM NTPs (ATP, CTP, and GTP), 100 µM UTP, and 400 µM digoxigenin-11-UTP at 37 C for 60 min. Template DNA was removed by adding 1 µl RQ1 deoxyribonuclease (Promega Corp.) and incubating at 37 C for 10 min. Probes were isolated by ethanol precipitation. Hybridizations were carried out for 12–16 h at 68 C in ULTRAhyb prehybridization/hybridization buffer (Ambion, Inc., Austin, TX). After hybridization, membranes were washed twice in 2 x SSC (standard saline citrate), twice in 0.5 x SSC-0.1% SDS at 65 C, and twice in 0.1 x SSC-0.1% SDS at 65 C. Membranes were incubated in blocking buffer [100 mM Tris-HCl (pH 7.5), 150 mM NaCl, and 5% blocking reagent from Roche Molecular Biochemicals] at room temperature for 30–60 min. Alkaline phosphatase-conjugated antibody against digoxigenin (Roche Molecular Biochemicals) was diluted 1:20,000 in blocking buffer and added to the membranes for 30 min at room temperature. Membranes were washed twice for 15 min each time in washing buffer [100 mM Tris-HCl (pH 7.5) and 150 mM NaCl] and equilibrated for 5 min in detection buffer [20 mM Tris-HCl (pH 9.5), 100 mM NaCl, and 50 mM MgCl2]. Membranes were placed between acetate sheets for the application of the chemiluminescent substrate CDP-Star (Roche Molecular Biochemicals) diluted 1:500 in detection buffer.

Tissues for in situ hybridization analysis were rapidly frozen on dry ice and stored at -80 C before preparing 20-µm sections on a cryostat. Tissue sections were air-dried before fixation in 4% paraformaldehyde in PBS for 5 min. After incubating in 2 x SSC for 5 min, the sections were dehydrated by a series of 50%, 70%, 95%, and 100% 3-min incubations. In situ hybridization was performed in a humidified chamber at 47 C for 12–16 h in a solution containing 50% formamide, 0.3 M NaCl, 10 mM Tris-HCl (pH 8.0), 1 mM EDTA, 1 x Denhardt’s solution (200 µg/ml each of Ficoll 400, polyvinylpyrrolidone, and BSA), 10% dextran sulfate, 10 mM dithiothreitol, 0.5 mg/ml yeast transfer RNA, 0.5 mg/ml poly(A) RNA, and 10 ng/ml denatured riboprobe. Slides were washed posthybridization in 2 x SSC for 10 min, followed by 20 µg/ml ribonuclease A digestion at 37 C for 1 h. Slides were then washed in 0.5 x SSC for 30 min, followed by a 1-h wash in 0.1 x SSC at 65 C. After incubating in blocking buffer (2 x SSC, 0.05% Triton X-100, and 0.1% BSA) for 1 h, alkaline phosphatase-conjugated antibody against digoxigenin was diluted 1:500 in blocking buffer and added to the tissue sections for 1 h at 37 C. Slides were washed for 10 min each in washing buffer and in detection buffer followed by incubation at 37 C with the alkaline phosphatase chromogenic substrate solution containing 250 µg/ml nitro blue tetrazolium and 225 µg/ml 5-bromo-4-chloro-3-indolyl-phosphate (Roche Molecular Biochemicals) until adequate staining was observed.

Yeast artificial chromosome (YAC) isolation and analysis
The YAC library (29) clones containing mouse genomic fragments corresponding to the PRL family locus were previously isolated (16). YAC-899 has a 700-kb insert that hybridizes to most PRL family member cDNAs, but not to PLF cDNA (28). DNA dot blots were prepared using a 96-well vacuum chamber (Schleicher & Schuell, Inc.). Yeast chromosomal DNA was purified by the "smash and grab" protocol (30). Samples of either 1 µg yeast DNA or 1 ng plasmid DNA were heated at 85 C for 15 min in 0.2 M NaOH and 1 mM EDTA. The samples were applied to a nylon membrane via the vacuum chamber and washed with 0.2 M NaOH. UV light was used to cross-link the DNA to the membrane. The ECL Direct Nucleic Acid Labeling and Detection System (Amersham Pharmacia Biotech, Piscataway, NJ) was used to generate probe DNA. Hybridization and washing of the DNA blots were performed according to the manufacturer’s instructions. Chemiluminescent peroxidase activity was detected using SuperSignal substrate (Pierce Chemical Co., Rockford, IL).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Identification of PLP-J
The amino acid sequence of PLF was used to screen a nonhuman, nonmouse EST database translated in all six reading frames to identify closely related sequences. A novel rat cDNA clone, EST UI-R-E0-BU-A-04–0-UI, was identified. Upon sequencing, the clone was found to contain a complete open reading frame for a 211-amino acid protein (Fig. 1Go). Analysis of the amino acid sequence suggests that the first 29 amino acids serve as a signal sequence and that N-linked glycosylation is possible, as consensus sites (Asn-X-Ser/Thr) exist at residues 48 and 144. Instead of naming the new clone PLP-I to follow the most recently identified PLP-H (17), which might be confused with either PL-I or PLP-1, we have designated this clone PLP-J. Using the rat clone to search a mouse EST database, a homologous clone, EST 569620, was identified. The mouse cDNA codes for a 212-amino acid protein that is predicted to have a 29-amino acid signal sequence. The 183-amino acid secreted form also may be glycosylated, as a single consensus site for N-linked modification exists at residue 71. Alignment of the mature rat and mouse proteins shows 68% overall identity (Fig. 2Go). Comparisons to PRL and related hormones confirm that PLP-J is a novel family member. Ironically, PLP-J’s most distant relation is PLF, with which only 18% of amino acids are conserved.



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  		Figure 1. Sequence of rat PLP-J. The nucleotide sequence of the PLP-J cDNA is shown with the numbering at the left of each line. The major open reading frame begins at the first ATG, and the predicted amino acid sequence is given in italics, with residue numbers above; negative numbers refer to the secretion signal sequence, which is predicted to be cleaved between Pro(-1) and Thr (1 ). The locations of consensus sites for N-linked glycosylation are indicated by the asterisks (Asn48 and Asn144). The consensus sequence for polyadenylation is underlined.

 


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  		Figure 2. Comparison of rat and mouse PLP-J protein sequences. The amino acid sequences of the secreted forms of rat and mouse PLP-J are aligned, with boxes marking sequence identities. Residue numbers are found at the right of each line.

 
Surprisingly, alignment of the rat and mouse PLP-J proteins to other members of the PRL family reveals that rat PLP-J lacks the C-terminal pair of cysteines characteristic of this hormone family. To test the validity of the rat sequence, we searched the nonmouse, nonhuman, EST database using rat PLP-J as the query sequence and identified seven EST clones identical to PLP-J. The predicted product of translation of each of the EST clones was found to yield C-termini identical to the predicted PLP-J amino acid sequence. In mouse PLP-J, Cys51 and Cys159 are predicted to form the large disulfide-linked loop; in the rat protein, the corresponding cysteines are located at positions 51 and 158. However, as also seen for PL-I (7), both forms of PLP-J have a cysteine five residues before the C-terminal cysteine partner of the predicted large loop. Consequently, it is possible that PLP-J lacks a disulfide linkage bridging the N- and C-termini, as is the case in PL-I (7). In mouse PLP-J, Cys169 and Cys183 are predicted to form the small loop; in the rat protein, no cysteines are found after Cys158. A cysteine residue is also found in both the mouse and rat forms of PLP-J at position 42, but is not present at this site in other related hormones. Rat PLP-J has two additional N-terminal cysteines, one found in the predicted secretion signal at position -10 and another at position 18.

Expression of PLP-J
No PLP-J expression was observed in RNA isolated from heart, lung, kidney, liver, muscle, spleen, thymus, or testis (data not shown). In placental/decidual tissue, expression of PLP-J mRNA was abundant on day 7 of gestation, slightly reduced on day 9, and undetectable from day 11 to the completion of gestation (Fig. 3Go). Hybridization to total RNA isolated from proestrous uterus and day 10 deciduoma revealed that PLP-J is detected specifically in the pseudopregnant uterus (Fig. 4Go). Hybridization to tissue sections from day 9 rat conceptus revealed that PLP-J is synthesized in the antimesometrial decidua immediately surrounding the site of implantation (Fig. 5Go, C and D). By delimiting the placental perimeter through hybridization to PL-II (Fig. 5Go, E and F), PLP-J expression appears to be solely decidual (Fig. 5Go, compare D and F). No signal was detected in hybridizations to the control sense strand of each probe, and no PLP-J mRNA synthesis could be detected in hybridizations to conceptus tissues from day 13, 15, or 17 (data not shown).



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  		Figure 3. Time course of PLP-J expression in placental/decidual tissue. Twenty micrograms of total RNA from placental/decidual tissues isolated on days 7–20 of rat gestation and during parturition were separated by denaturing gel electrophoresis, transferred to a filter, and hybridized to PLP-J riboprobe (upper panel). Equal loading of RNA was verified by ethidium bromide staining (lower panel).

 


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  		Figure 4. PLP-J expression in rat pseudopregnancy. Twenty micrograms of total RNA from day 9 placental/decidual tissue, proestrous uterus, and day 10 pseudopregnant uterus were separated by denaturing gel electrophoresis, transferred to a filter, and hybridized to the PLP-J riboprobe (upper panel). Equal loading of RNA was verified by ethidium bromide staining (lower panel).

 


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  		Figure 5. Cell-specific pattern of PLP-J expression. Digoxigenin-labeled sense (A and B) or antisense (C and D) PLP-J or antisense PL-II (E and F) RNA was used to hybridize to 20-µm sections from a day 9 rat conceptus. Hybridization was detected with antidigoxigenin coupled to alkaline phosphatase, which catalyzed a chromogenic reaction resulting in dark purple cells. The mesometrial pole (mp), antimesometrial pole (amp), and embryo (e) are indicated. Primary giant cells found in both high power sections are indicated by the arrows. Bar, 100 µm.

 
Mapping of the PLP-J gene
All of the genes in the PRL family in the mouse have been mapped to chromosome 13 at 14.0 centimorgans (31, 32). YAC-899 contains an insert of 700 kb from this locus that includes many of the PRL family genes, such as PRL, PL-I, PL-II, and PRP (28). Similar to the PRP control, PLP-J cDNA hybridizes to DNA from the yeast strain carrying YAC-899, but not to DNA from a control yeast strain (Fig. 6Go).



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  		Figure 6. Chromosomal mapping of PLP-J. DNAs were immobilized on a filter and hybridized to horseradish peroxidase-labeled mouse PLP-J cDNA (upper panel) or to PRP cDNA (lower panel; positive control). Lane 1, Mouse PRL cDNA; lane 2, mouse PLF cDNA; lane 3, mouse PRP cDNA; lane 8, mouse PLP-J cDNA; lanes 4, 6, 7, and 9, control unrelated cDNAs; lanes 5 and 10, yeast genomic DNA. YAC-899 is total DNA from a yeast clone that includes a YAC with a 700-kb region of mouse genomic DNA encompassing the mouse PRL gene and nearby genes.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The addition of PLP-J to the PRL family of placental/decidual hormones in the rodent increases the total number of distinct family members identified to 16 (PL-I, PL-Iv, PL-II, PLF, PRP, dPRP, PLP-A, PLP-B, PLP-C, PLP-Cv, PLP-C{alpha}, PLP-D, PLP-E, PLP-F, PLP-H, and PLP-J). The PLP-J gene is located within a 700-kb region at 14.0 centimorgans on mouse chromosome 13 near many other related genes, including the genes encoding PRL, PL-I, PL-II, dPRP, PRP, PLP-B, PLP-E, and PLP-F. Four to six copies of the PLF gene are also found at the same chromosomal locus but outside of the 700-kb region (28). In the rodent, duplication of the PRL gene with subsequent divergence is the likely root of the hormone family. In the human, the known members of the PRL/GH family (excluding PRL) are all situated at the GH gene locus (found on chromosome 11 in the mouse) (31); thus, it is not altogether surprising that human homologs to many of the rodent PRL family members have not been identified.

Characteristics of PLP-J that mark it as a member of the larger cytokine superfamily are the predicted cleavable hydrophobic secretion signal sequence, the presence of asparagine-coupled carbohydrate linkages, and the definitive highly conserved cysteine residues. Rat PLP-J is most closely related to PL-I, with 36% amino acid sequence identity between secreted hormones (for comparison, PL-I and PL-II have 37% identity). On the other hand, mouse PLP-J has a less remarkable 28% identity to mouse PL-I. However, 68% of the rat and mouse PLP-J amino acid sequences is identical, suggesting an overall conservation of function.

PLP-J expression in the rat is detected exclusively in the decidua. Decidualization occurs under the influence of progesterone and estrogen in response to uterine stimuli or in anticipation of blastocyst implantation (33). Two histologically distinct zones of decidualization are observed. The primary decidual zone is observed on day 5 of gestation. It consists of the antimesometrial decidua (AMD), which is characterized by the proliferation and differentiation of uterine stromal cells surrounding the implantation site into large, multinucleate cells. Two days subsequent to AMD formation, the mesometrial decidua forms. Before the invasion of the mesometrial decidua by placental trophoblasts, the metabolic needs of the developing embryo are met in part by an increase in vascular permeability in the primary decidual zone and the accumulation of stores of glycogen by decidual cells (34). Several other functions for the decidua have been proposed. Decidual factors may play a role in the immunomodulation of the maternal response to paternal antigens present in embryonic tissues. In addition, decidually derived factors may have a role in coordinating and limiting the amount of vascular invasion (35). Tissue inhibitor of matrix metalloproteinase 3 expression is markedly increased in the AMD between days 5–8 of mouse gestation (36). In the case of participants in the plasmin/plasminogen system, spatio/temporal decidual expression data suggest a crucial role in the regulation of invasiveness and vessel repair (37). However, mice with homozygous deletion of individual factors involved in the regulation of plasmin activation, such as urokinase-type plasminogen activator (38), plasminogen activator inhibitor-1 (39), plasminogen (40, 41), or {alpha}2-macroglobulin (42), have normal pregnant tissue and successful gestations. Such protective redundancy is beneficial to dampening local variability during trophoblast invasion, ensuring the proper establishment of a hemochorial placenta able to meet the increasing metabolic demands of the growing embryo.

In the pregnant animal, PLP-J expression is limited to the antimesometrial decidua. Maximal expression was detected on day 7, the earliest time point examined, after which expression decreased to an undetectable level by day 11. The temporal expression data are in agreement with the timing of antimesometrial apoptosis, necrosis, and degradation (43). The timing and location of PLP-J expression is similar to those of dPRP (mouse) (28), d/tPRP (rat) (27), and PLP-B (11, 28). Similar to dPRP and in contrast with d/tPRP and PLP-B, by the time of true chorioallantoic placentation, synthesis of PLP-J is no longer detectable, whereas d/tPRP and PLP-B expression switches from maternal to extraembryonic tissue.

The placenta resembles a pharmacological organ, in that it secretes high amounts of factors over a limited time span that probably act on existing maternal targets to bring about the physiological changes of pregnancy (1). It appears that the AMD may serve a parallel function. As the source of several PRL family hormones as well as galanin (44), activin (45, 46), follistatin (45, 46), and decidual luteotropin (DLt) (47), the AMD appears to be an independent endocrine organ. Indeed, the colocalization and similar timing of PLP-J and DLt expression raise the possibility that DLt, which has PRL-like activity (48, 49) but has not yet been cloned, and PLP-J may be the same. If PLP-J proves to be distinct from DLt, then the discovery of PLP-J may serve to identify additional important molecular and cellular targets involved in realizing the diverse changes associated with pregnancy.


   Acknowledgments
 
We thank Diane M. Mayer and Janelle Roby for expert technical assistance, Jiandie Lin for thoughtful discussions, and Kelly Mayo for pseudopregnant decidual RNA.


   Footnotes
 
1 The complete sequences for the mouse and rat PLP-J cDNAs have been submitted to GenBank and assigned accession no. AF150740 for mouse PLP-J and AF150741 for rat PLP-J. This work was supported by NIH Grants HD-29962 and HD-24518 and by the NIH P30 Research Center on Fertility and Infertility at Northwestern University (Grant HD-28048). Back

Received May 24, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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