Endocrinology Vol. 138, No. 12 5535-5540
Copyright © 1997 by The Endocrine Society
Two Novel Members of the Prolactin/Growth Hormone Family Are Expressed in the Mouse Placenta1
Jiandie Lin,
Jason Poole 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
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Abstract
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Two novel members of the mouse PRL/GH family have been identified
through a search of an expressed sequence tag database. The encoded
proteins do not appear to be homologs of other known members of this
hormone family. One of these proteins, designated PRL-like protein E
(PLP-E), is predicted to be synthesized as a precursor of 265 amino
acids, modified by N-linked glycosylation, and secreted
as a mature glycoprotein of 236 residues. The second clone encodes a
protein of 253 residues with consensus sites for
N-linked glycosylation; the secreted form of the
protein, designated PRL-like protein F (PLP-F), is predicted to be 223
amino acids in length. Both of these messenger RNAs are expressed
specifically in the placenta, with peak levels of PLP-E on days 10–12
and of PLP-F on days 14–16. Expression of PLP-E is restricted to the
trophoblast giant cells, whereas PLP-F is synthesized only in the
spongiotrophoblasts. The genes for both of these proteins map to a
700-kilobase region of mouse chromosome 13 that includes other members
of the PRL/GH family.
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Introduction
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THE PLACENTA of many rodents, ruminants,
and primates is a source of hormones in the PRL/GH family. The number
of different placental hormones can be quite large; the rat placenta
and decidua produce at least nine distinct hormones related to PRL
(1, 2, 3, 4, 5, 6, 7, 8, 9), and seven hormones in this family have been identified in the
cow placenta (10, 11, 12, 13, 14, 15, 16). The synthesis of only four members of this
hormone family, placental lactogen I (PL-I), PL-II, proliferin (PLF),
and PLF-related protein (PRP), has been discovered in the mouse
placenta (17, 18, 19, 20), but three additional members, PRL-like protein A
(PLP-A), PLP-B, and decidual PRL-related protein (dPRP), are reported
in the accompanying paper (20a).
The function and expression of these four mouse placental PRL-like
hormones have been studied extensively. PL-I and PL-II bind to the PRL
receptor (21, 22) and display PRL-like bioactivities that include
stimulating progesterone production by the corpus luteum (23), inducing
insulin secretion (24), and promoting maternal mammary gland
development in preparation for postpartum lactation (25). PL-I is
synthesized specifically in the trophoblast giant cells beginning at
the implantation stage (26, 27), and levels of this hormone messenger
RNA (mRNA) and circulating protein peak at midpregnancy (20, 28). PL-II
synthesis also occurs only in the giant cells (29), but transcription
of the PL-II gene begins at midpregnancy and continues at a high level
until term (19).
The other two characterized hormones, PLF and PRP, are, respectively,
positive and negative regulators of angiogenesis (30). Based on an
endothelial cell chemotaxis assay, PLF represents the majority of the
angiogenic activity released by the midpregnant mouse placenta (30).
This hormone binds to blood vessels in the placenta and fetus (30, 31)
and is important for decidual neovascularization (32). The patterns of
PLF and PL-I synthesis are similar, as PLF is produced only by giant
cells beginning at the implantation stage (27, 33), and PLF mRNA and
protein both accumulate at a maximum level on day 10 (33). Synthesis of
PRP, which is the major antiangiogenic factor secreted by the late
pregnant mouse placenta (30), occurs later in gestation than that of
PLF and in both giant cells and spongiotrophoblasts (18, 27, 34). One
role for PRP may be as a temporal brake on the process of
neovascularization, but the expression of PRP throughout two cell
layers also suggests that PRP may act to establish a zone through which
maternal and fetal vessels cannot cross.
As placental hormones related to PRL have important functions during
pregnancy, and a number of hormones in this family from other species
have not yet been detected in the mouse, we set out to find additional
PRL-like hormones that are produced in the mouse placenta. In the
accompanying paper (20a), we report on three new mouse hormones that
are closely related to proteins that had been identified in the rat.
Here, we characterize two additional complementary DNA (cDNA) clones
that encode novel members of the mouse PRL/GH family that are expressed
specifically in the placenta.
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Materials and Methods
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Animals and animal care
Pregnant Swiss-Webster mice of defined gestational stages were
purchased from Charles River Laboratories (Wilmington, MA). Mice were
maintained on days of 14 h of light and 10 h of darkness,
with food and water freely available. All procedures were approved by
the Northwestern University animal care and use committee. Mouse
tissues for RNA analysis were rapidly frozen on dry ice after removal
from the animal and stored at -80 C until use.
Database screening and DNA sequence analysis
An expressed sequence tag (EST) database accessed through
the internet at the National Center for Biotechnology Information
(http://www.ncbi.nlm.nih.gov/cgi-bin/BLAST/nph-blast?Jform = 0)
was searched for sequences related to known members of the mouse PRL
family. Retrieved sequences were compared with previously characterized
members of the PRL family to identify clones that represent novel
mRNAs. Two such clones were identified and obtained from Genome Systems
(St. Louis, MO); we have designated these clones PLP-E (EST mo52d02.r1,
GenBank no. AA111551, clone identification no. 557187) and PLP-F (EST
mh20d02.r1, GenBank no. AA014234, clone identification no. 443043).
Plasmid DNAs were purified and sequenced using vector-specific
oligonucleotides as primers; primers derived from the ends of the cDNA
sequence were then synthesized to generate the remaining sequence.
Computer analysis of the sequences was carried out with GeneWorks
(Intelligenetics, Mountain View, CA).
RNA and DNA hybridization
Detailed procedures for the analysis of tissue RNA by filter and
in situ hybridizations are provided in the accompanying
paper (20a). The accompanying paper also describes the isolation and
analysis of a yeast artificial chromosome, designated YAC-899, that
contains a 700-kilobase (kb) fragment of mouse chromosome 13 that
includes most of the genes in the PRL family.
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Results
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Identification of mouse PLP-E and PLP-F
Two novel cDNA clones closely related to PRL were identified
in a mouse conceptus EST database. EST mo52d02.r1 has a single major
open reading frame for a 265-amino acid protein (Fig. 1
). Comparison of this protein to mouse
PRL and other related hormones establishes that the encoded protein is
a novel member of this hormone family (Fig. 3A), and alignment of the
sequences suggests that the first 29 amino acids serve as a secretion
signal sequence. The secreted protein of 236 amino acids, which we have
designated PLP-E, is likely to be heavily glycosylated, as consensus
sites for N-linked glycosylation (Asn-X-Ser/Thr) are present
at positions 6, 28, 80, 119, 127, and 234.
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Figure 1. Sequence of mouse PLP-E. The nucleotide sequence
of PLP-E cDNA is shown with 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
Cys(-1) and Leu(1). The six consensus sites for N-linked
glycosylation are marked by asterisks. The consensus
sequence for polyadenylation is underlined.
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Figure 3. Comparison of mouse protein sequences. A, For PRL
and all of the known placental proteins related to PRL, the percent
amino acid sequence identity between each pair of hormones is given.
Comparisons were made between the sequences of the secreted proteins
and, therefore, do not include matches within the signal sequence. The
percent identity between PLP-E and PLP-F is highlighted.
B, The amino acid sequences of the secreted forms of mouse PLP-E and
PLP-F are aligned, with boxes marking sequence
identities.
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The primary translation product predicted from the second clone, EST
mh20d02.r1, is 253 residues, including a signal sequence of 30 amino
acids (Fig. 2). The putative mature
protein of 223 amino acids has three potential sites of
N-linked glycosylation (residues 6, 73, and 105). This
protein is also significantly similar in sequence to PRL and related
hormones (Fig. 3A
), and therefore, we
have called it PLP-F. Surprisingly, within this hormone family PLP-E
and PLP-F show the greatest degree of sequence similarity with each
other (54% identity, a degree of similarity that is much greater than
that between any other two family members; Fig. 3A), suggesting that
these two proteins define a new subfamily.
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Figure 2. Sequence of mouse PLP-F. The nucleotide sequence
of the PLP-F cDNA is shown with 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
Ser(-1) and Val(1). The three consensus sites for
N-linked glycosylation are marked by
asterisks. The consensus sequence for polyadenylation is
underlined.
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One of the hallmarks of proteins in the PRL family is the
occurrence of one large disulfide loop and a small carboxy-terminal
disulfide loop. Both PLP-E and PLP-F have cysteine residues that align
with those found in the other members of the family. In PLP-E,
Cys84 and Cys201 are predicted to form the
large loop, and Cys218 and Cys227 to form the
small loop; in PLP-F, the corresponding cysteines are located at
residues 71 and 188, and 205 and 214. However, both of these proteins
have additional cysteines that may form covalent intramolecular
interactions that are not typically found among members of this family.
Cys196 in PLP-E and Cys183 in PLP-F align (Fig. 3B), and these residues may interfere with the formation of the large
disulfide loop, similar to what has been found in mouse PL-I (20).
PLP-F is unique among family members in having an extra cysteine (at
position 70) immediately adjacent to the upstream conserved cysteine
(at position 71) that participates in the large loop.
Expression of PLP-E and PLP-F
Total RNA was isolated from several pregnant mouse tissues,
separated by denaturing gel electrophoresis, transferred to a membrane,
and hybridized to the PLP-E and PLP-F cDNAs. Expression of both of
these cDNAs is restricted to the placental/decidual tissue (Fig. 4); in addition to the tissue RNAs shown
in Fig. 4, pituitary RNA was also found to be negative for the PLP-E
and PLP-F mRNAs (data not shown). PLP-E synthesis precedes that of
PLP-F, with PLP-E mRNA present at high levels in the placenta on days
8–12 of gestation, and PLP-F mRNA present at maximal levels on days
14–16 (Fig. 5). Hybridization to tissue
sections reveals that during its peak expression on days 10 and 12 of
pregnancy, PLP-E is synthesized only in the trophoblast giant cells
(Fig. 6, A and B). In contrast, PLP-F
synthesis is only detected in the spongiotrophoblasts of the day 15
placenta (Fig. 6C).
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Figure 4. Tissue-specific pattern of PLP-E and PLP-F
expression. Twenty micrograms of total RNA from the indicated tissues
were separated by denaturing gel electrophoresis, transferred to a
filter, and hybridized to the PLP-E or PLP-F cDNA. The loading of equal
amounts of intact RNA in each lane was verified by staining the filter
with methylene blue. The major hybridizing band for PLP-E and PLP-F is
1 kb.
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Figure 5. Time course of PLP-E and PLP-F expression in the
placenta. Twenty micrograms of total RNA from placental/decidual
tissues isolated from days 8–18 of gestation were separated by
denaturing gel electrophoresis, transferred to a filter, and hybridized
to the PLP-E or PLP-F cDNA. Equal RNA loading was verified by staining
(not shown).
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Figure 6. Cell-specific pattern of PLP-E and PLP-F
expression. Twenty-five-micron sections through day 10 (A), day 12 (B),
and day 15 (C) implantation sites were hybridized to single stranded,
digoxigenin-labeled, antisense PLP-E (A and B) or PLP-F (C) RNA.
Hybridization (dark purple cells) was detected with antidigoxigenin
coupled to alkaline phosphatase. The decidual tissue (d) of the uterus
and the giant cell (g), spongiotrophoblast (s), and labyrinth (la)
regions of the placenta are indicated. The bar in the lower
righthand corner of each panel corresponds to 100 µm.
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Mapping of the PLP-E and PLP-F genes
A yeast artificial chromosome (YAC-899) has been
identified with an insert of 700 kb from mouse chromosome 13 that
includes the genes for PRL, PL-I, PL-II, PRP, PLP-B, and dPRP (20a).
DNA from the yeast strain carrying YAC-899, but not DNA from a control
yeast strain, hybridizes to the PLP-E and PLP-F cDNAs (Fig. 7). Note that despite the strong sequence
similarity between PLP-E and PLP-F (75% at the nucleotide level within
the coding region), the two cDNAs do not cross-hybridize under these
conditions. Thus, the PLP-E and PLP-F genes also map to the region of
chromosome 13 that contains a cluster of genes related to PRL.
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Figure 7. Chromosomal mapping of the PLP-E and PLP-F genes.
DNAs were immobilized on a filter and hybridized to PLP-E cDNA
(upper panel), PLP-F cDNA (middle panel),
or PRL cDNA as a positive control (lower panel). The
immobilized DNAs are indicated above the filters.
YAC-899 contains 700 kb of mouse DNA from chromosome 13, including the
PRL, PL-I, PL-II, and PRP genes; DNA from a yeast strain lacking this
YAC serves as a negative control.
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Discussion
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With the identification of two novel cDNAs, the mouse PRL/GH
now has nine known members that are expressed specifically in the
placenta or decidua: PL-I, PL-II, PLF, PRP, PLP-A, PLP-B, dPRP, PLP-E,
and PLP-F. The PLP-E and PLP-F genes along with the genes for PRL,
PL-I, PL-II, PRP, PLP-B, and dPRP are located within a 700-kb region at
14.0 centimorgans on mouse chromosome 13 (20a, 35, 36); the chromosomal
position of the PLP-A gene is not known, and the multicopy PLF genes
(37), although also present on chromosome 13 near this hormone gene
cluster (35, 36), lie outside of this 700-kb region (20a).
As PLP-E and PLP-F are most closely related to each other in sequence,
with greater than 50% amino acid sequence identity between the
secreted proteins and 75% nucleotide sequence identity between the
coding regions of the two mRNAs, these two proteins appear to represent
a new subclass of PRL-related hormones. Possibly, these genes arose
from a more recent duplication event and, consequently, have not
diverged as much from each other as have other genes in this family.
Alternatively, the sequences of PLP-E and PLP-F have been conserved
through selection for continued function of these proteins. Each of
these proteins is predicted to be synthesized with a cleavable,
hydrophobic secretion signal sequence, and each is expected to be
modified by the covalent attachment of carbohydrate at several
asparagine residues. Although the four highly conserved cysteine
residues in this hormone family are also found in PLP-E and PLP-F, the
presence of additional cysteines (one in PLP-E, two in PLP-F) may
contribute to a distinct pattern of intramolecular disulfide bonds.
Both PLP-E and PLP-F are expressed specifically in the placenta,
but they are synthesized in different cells and at different
gestational stages. PLP-E mRNA has only been detected in the
trophoblast giant cells, and expression is highest at midpregnancy. The
location and timing of PLP-E expression are very similar to patterns of
PL-I (20) and PLF (33) synthesis. As transcription of the PL-I and PLF
genes is regulated by activating protein-1 (38, 39, 40) and GATA-2/GATA-3
(32, 41), it seems likely that the PLP-E gene will also be responsive
to these transcription factors. PLP-F synthesis is not detected until
later in gestation, and only in the spongiotrophoblasts; transcription
of the PLP-F gene may, therefore, be regulated similarly to the late
gestation expression of PRP (34) and PLP-B (20a) in the
spongiotrophoblasts, but the factors regulating transcription of the
PRP and PLP-B genes in this cell type are not known.
At present, any biological and physiological functions of PLP-E and
PLP-F are speculative. It seems unlikely that PLP-E and PLP-F regulate
blood vessel growth, as the majority of angiogenic and antiangiogenic
activity secreted by the mouse placenta has already been accounted for
by PLF and PRP (30). Also, because the hormones that bind to the PRL
receptor and display PRL-like activity have been purified and
identified as PL-I and PL-II (42, 43), PLP-E and PLP-F probably do not
interact with the PRL receptor and do not have lactogenic activity.
Therefore, PLP-E and PLP-F may well have novel receptor specificities
and effects. However, as PLP-E and PLP-F are closely related in
sequence, these two proteins may have similar targets and actions.
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Acknowledgments
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We thank Anuja Dharkar and Janelle Roby for expert technical
assistance, and Jordan Shavit and Doug Engel for help with the YAC
cloning and analysis.
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Footnotes
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1 This work was supported by NIH Grant HD-29962, the P30 Research
Center on Fertility and Infertility at Northwestern University
(HD-28048), and the Robert H. Lurie Cancer Center (P30-CA-60553). The
complete sequences for the mouse PLP-E and PLP-F cDNAs have been
submitted to GenBank, and they have been assigned accession no.
AF011381 and AF011382, respectively. 
Received May 19, 1997.
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B. Zhou, X. Kong, and D. I. H. Linzer
Enhanced Recovery from Thrombocytopenia and Neutropenia in Mice Constitutively Expressing a Placental Hematopoietic Cytokine
Endocrinology,
January 1, 2005;
146(1):
64 - 70.
[Abstract]
[Full Text]
[PDF]
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T. L. Kroft, S. Li, L. Doglio, and E. Goldberg
A Transgenic Analysis of Mouse Lactate Dehydrogenase c Promoter Activity in the Testis
J Androl,
November 1, 2003;
24(6):
843 - 852.
[Abstract]
[Full Text]
[PDF]
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A. Ozturk, A. Fresnoza, A. Savoie, H. W. Duckworth, and M. L. Duckworth
Defining Regulatory Regions in the Rat Prolactin Gene Family Locus Using a Large P1 Genomic Clone
Endocrinology,
November 1, 2003;
144(11):
4742 - 4754.
[Abstract]
[Full Text]
[PDF]
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D. O. Wiemers, L.-j. Shao, R. Ain, G. Dai, and M. J. Soares
The Mouse Prolactin Gene Family Locus
Endocrinology,
January 1, 2003;
144(1):
313 - 325.
[Abstract]
[Full Text]
[PDF]
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B. Zhou, H. E. Lum, J. Lin, and D. I. H. Linzer
Two Placental Hormones Are Agonists in Stimulating Megakaryocyte Growth and Differentiation
Endocrinology,
November 1, 2002;
143(11):
4281 - 4286.
[Abstract]
[Full Text]
[PDF]
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S. Bhattacharyya, J. Lin, and D. I. H. Linzer
Reactivation of a Hematopoietic Endocrine Program of Pregnancy Contributes to Recovery from Thrombocytopenia
Mol. Endocrinol.,
June 1, 2002;
16(6):
1386 - 1393.
[Abstract]
[Full Text]
[PDF]
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L. Gambling, Z. Charania, L. Hannah, C. Antipatis, R. G. Lea, and H. J. McArdle
Effect of Iron Deficiency on Placental Cytokine Expression and Fetal Growth in the Pregnant Rat
Biol Reprod,
February 1, 2002;
66(2):
516 - 523.
[Abstract]
[Full Text]
[PDF]
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D. J. Toft and D. I.H. Linzer
Identification of Three Prolactin-Related Hormones as Markers of Invasive Trophoblasts in the Rat
Biol Reprod,
August 1, 2000;
63(2):
519 - 525.
[Abstract]
[Full Text]
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J. T. FASSETT, R. T. HAMILTON, and M. NILSEN-HAMILTON
Mrp4, A New Mitogen-Regulated Protein/Proliferin Gene; Unique in this Gene Family for its Expression in the Adult Mouse Tail and Ear
Endocrinology,
May 1, 2000;
141(5):
1863 - 1871.
[Abstract]
[Full Text]
[PDF]
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Y. Su, S. A. Liebhaber, and N. E. Cooke
The Human Growth Hormone Gene Cluster Locus Control Region Supports Position-independent Pituitary- and Placenta-specific Expression in the Transgenic Mouse
J. Biol. Chem.,
March 10, 2000;
275(11):
7902 - 7909.
[Abstract]
[Full Text]
[PDF]
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D. J. Toft and D. I. H. Linzer
Prolactin (PRL)-Like Protein J, a Novel Member of the PRL/Growth Hormone Family, Is Exclusively Expressed in Maternal Decidua
Endocrinology,
November 1, 1999;
140(11):
5095 - 5101.
[Abstract]
[Full Text]
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J. Lin and D. I. H. Linzer
Induction of Megakaryocyte Differentiation by a Novel Pregnancy-specific Hormone
J. Biol. Chem.,
July 23, 1999;
274(30):
21485 - 21489.
[Abstract]
[Full Text]
[PDF]
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G. Dai, B. M. Chapman, B. Liu, K. E. Orwig, D. Wang, R. A. White, B. Preuett, and M. J. Soares
A New Member of the Mouse Prolactin (PRL)-Like Protein-C Subfamily, PRL-Like Protein-C{alpha}: Structure and Expression
Endocrinology,
December 1, 1998;
139(12):
5157 - 5163.
[Abstract]
[Full Text]
[PDF]
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J. Lin and D. I. H. Linzer
Identification of Trophoblast-Specific Regulatory Elements in the Mouse Placental Lactogen II Gene
Mol. Endocrinol.,
March 1, 1998;
12(3):
418 - 427.
[Abstract]
[Full Text]
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J. Lin, J. Poole, and D. I. H. Linzer
Three New Members of the Mouse Prolactin/Growth Hormone Family Are Homologous to Proteins Expressed in the Rat
Endocrinology,
December 1, 1997;
138(12):
5541 - 5549.
[Abstract]
[Full Text]
[PDF]
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Top
Abstract
Introduction
