Blackwell Publishing AsiaMelbourne, AustraliaASJAnimal Science Journal1344-39412005 Blackwell Publishing Asia Pty LtdFebruary 20057711017Review Article BOVINE PLACENTAL

LACTOGENT. TAKAHASHI

Animal Science Journal (2006) 77, 1017

doi: 10.1111/j.1740-0929.2006.00314.x

REVIEW ARTICLE Biology of the prolactin family in bovine placenta. I. Bovine placental lactogen: Expression, structure and proposed roles
Toru TAKAHASHI
National Institute of Agrobiological Sciences, Tsukuba-shi, Japan

ABSTRACT
Bovine placenta produces an array of proteins that are structurally and functionally similar to pituitary prolactin. Bovine placental lactogen (bPL) is a glycoprotein hormone that has lactogenic and somatogenic properties. Puried bPL contains several kinds of isoforms that are created by alternative splicing and/or multiple glycosylation patterns. bPL can activate the prolactin (PRL) receptor-mediated signaling pathway as well as PRL does. The bPL mRNA is transcribed in trophoblast binucleate cells, and synthesized bPL protein is stored in membrane-bound secretory granules. The message encoding bPL is rst detectable in trophoblast binucleate cells at approximately day 20 of gestation at, or shortly after, the appearance of binucleate cells in the trophoblast. Most binucleate cells are detected as expressed bPL in the placenta. Bovine PL may be the determinant in trophoblast differentiation. Although the biological activities of bPL have long been studied, the precise role of bPL is still largely unclear. This article reviews and discusses the biological roles of bPL, focusing on luteal function, fetal growth and pregnancy-associated maternal adaptation, mammogenesis and lactogenesis, and placental angiogenesis. The precise biological function of bPL needs to be further evaluated.

Key words: bovine, placenta, placental lactogen, prolactin.

HISTORICAL BACKGROUND
The placenta produces an array of proteins during gestation. In horses, primates, rodents and ruminants, the placenta expresses pituitary hormones or members of their large paralog families (Aschheim & Zondek 1928; Cole & Hart 1930; Kohmoto & Bern 1970; Buttle & Forsyth 1976). Placental hormones structurally and functionally similar to pituitary prolactin (PRL) are known as placental PRL family proteins. Placental PRL family proteins were rst identied because the mammotropic action of placental tissue when co-cultured with mammary gland explants was noted (Josimovich & Maclaren 1962). Therefore, this placenta-derived lactogenic hormone was named placental lactogen (PL). However, because PL from some species also exhibit somatogenic activity, the term chorionic somatomammotropic hormone is also used to describe PL, especially in gene databases (e.g. GenBank). Cur-

rently, PL has been detected in primates, rodents and ruminants, but not in rabbits or dogs (Talamantes 1975). However, the existence of bovine PL (bPL) remained unclear until the mid-1970s, although rodent and primate PL were identied earlier (Buttle & Forsyth 1976). Shortly after the discovery of bPL, bPL protein was puried by some groups (Bolander & Fellows 1976; Eakle et al. 1982; Murthy et al. 1982; Arima & Bremel 1983). Subsequently, molecular cloning of bPL was carried out in the late 1980s (Schuler & Hurley 1987; Schuler et al. 1988). In the present paper, I review the structure, expression prole and biological roles of bPL.
Correspondence: Toru Takahashi, Reproductive Biology and Technology Laboratory, Developmental Biology Department, National Institute of Agrobiological Sciences, Tsukuba-shi, 305-0901, Japan. (Email: tatoru@affrc.go.jp) Received 11 October 2005; accepted for publication 25 October 2005.

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STRUCTURE OF BOVINE PLACENTAL LACTOGEN

Early bPL purication studies produced estimates of the molecular weight of bPL that varied from 22 150 (Bolander & Fellows 1976) to 45 000 (Hayden & Forsyth 1979) to 60 000 (Roy et al. 1977), as measured by gel ltration chromatography in the presence of a denaturant. However, more recent reports employing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) have revised the molecular weight to approximately 32 000 in both placental explant culture and puried materials (Eakle et al. 1982; Murthy et al. 1982; Arima & Bremel 1983). The discrepancies in past estimates of the molecular size of bPL are believed to be a result of the lower purication yield of the material and the differences in the procedures for molecular size estimation. Molecular cloning studies using cDNA encoding bPL predict a prepro-bPL of 236 amino acids, with a 36-amino acid signal peptide (Schuler et al. 1988). The bPL amino acid sequence has 51% identity with bPRL, and 22% identity with both human PRL and bovine growth hormone (bGH). bPL has a consensus N-glycosylation site and many potential sites for Oglycosylation, where carbohydrate chains are added. This is in contrast to the pituitary members of the PRL gene family and some placental PRL family proteins of other species (Duckworth et al. 1986; Soares et al. 1998). Carbohydrate chains appear to delay the biological clearance of proteins to maintain availability at the target tissue. The presence of bPL isoforms, which differ from the major form with respect to both molecular size and electrical charge, has been reported (Byatt et al. 1986, 1990). The bPL secreted from the placenta seems to be heterogenous. Two-dimensional gel electrophoresis of intact bPL reveals molecules with two different molecular weights (29 000 and 32 000), and the difference remains after enzymatic deglycosylation (Byatt et al. 1990). Kessler and Schuler (1991) reported the presence of truncated bPL transcripts comprising 13% of total bPL mRNA in mid-pregnancy placenta. Additionally, bPL isoforms with the same molecular size and different pI values were also found to be present in placental tissues (Byatt et al. 1986, 1990). This appears to be a result of multiple glycosylation patterns during post-translational modication. Therefore, the existence of multiple isoforms of bPL is a result of at least two distinct causes. In SDS-PAGE under reducing conditions, native bPL secreted by the placenta migrated

with an apparent molecular weight of 32 000, whereas recombinant bPL produced in Escherichia coli, which is not glycosylated, migrated with a molecular weight of 26 000 (Byatt et al. 1991). Interestingly, under nonreducing conditions, E. coli-derived bPL migrates with an apparent molecular weight of 22 000 (Byatt et al. 1991). The deduced molecular weight of deglycosylated bPL is approximately 22 000. Recombinant bPL migrates according to its real molecular weight under non-reducing conditions rather than under reduced conditions. This curious migration behavior in SDSPAGE may be associated with the amino acid sequence and the 3-D structure of bPL.

RECEPTOR-BINDING CHARACTERISTICS
Binding to the PRL receptor is one of the principal biochemical characteristics of bPL. Therefore, the Nb2 lymphoma cell bioassay, for assaying lactogenic hormones, is a suitable tool for assaying bPL in both plasma and explant culture medium (Schellenberg & Friesen 1982; Takahashi et al. 2001). The lactogenic activity of bPL is almost equipotent to that of highly puried ovine PRL (Schellenberg & Friesen 1982). Because bPL has structural and functional similarities to bPRL, it may have evolved from the ancestral gene of the PRL lineage (Soares et al. 1998). Several new members of the bovine PRL gene family other than bPL have been reported (for review, see Ushizawa & Hashizume 2006 in this issue). It is likely that new members of the PRL family have been generated by gene duplication from PRL (Wallis 1992). This speculation is supported by the evidence that bPRL, bPL and bGH co-locate on chromosome 23 (Dietz et al. 1992). Among these members of the bovine placental PRL family, to our knowledge, bPL is the only member of the classical (lactogenic) group. However, bPL also has somatogenic properties (Ogren & Talamantes 1988; Staten et al. 1993) in addition to lactogenic ones, and its amino acid sequence has approximately 20% identity with that of bGH (Schuler et al. 1988). In primates, human PL (hPL) has an afnity to human GH (hGH) binding protein, which is present at a 2300-fold lower concentration than hGH, although the amino acid sequence of hPL has 85% identity with that of hGH (Lowman et al. 1991). Ovine PL (oPL) also binds with high afnity to primate and rodent GH receptors (Ogren & Talamantes 1988; Colosi et al. 1989). The amino acid residues, or binding domain of ruminant PL associated with binding to the GH

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receptor, remain unclear. Gofn et al. (1996) suggest that the binding of ruminant PL to GH receptors does not require a specic residue/domain for hormone receptor interactions. However, ruminant PL are not able to activate ovine GH receptor-mediated biological actions or act as antagonists, although they can activate GH receptor-mediated biological activities in humans and rabbits (Herman et al. 1999). Because ruminant PL binds to the ovine GH (oGH) receptor at a ratio of 1:1, ruminant PL antagonize the binding of oGH to the oGH receptor and occupy the receptor without inducing the homodimerization of receptors.

SOURCE OF EXPRESSION
The bPL mRNA is transcribed in trophoblast binucleate cells (Yamada et al. 2002) and synthesized bPL protein is stored in membrane-bound secretory granules in these cells (Wooding 1982). At approximately day 60 of gestation, most of the binucleate cells (>95%) express bPL protein, whereas no expression is detected in mononucleate cells (Yamada et al. 2002). Additionally, the expression of bPL co-localizes with that of pregnancy-associated glycoprotein (bPAG)-1 in the same binucleate trophoblast (Yamada et al. 2002). The mRNA encoding bPL is rst detectable with in situ hybridization in trophoblast binucleate cells at approximately day 20 of gestation (Yamada et al. 2002). Similarly, bPL protein is also detectable on the same day (Flint et al. 1979; Yamada et al. 2002), at or shortly after the appearance of binucleate cells in the trophoblast. It has been reported that the number of binucleate cells expressing PL decreases during late gestation in ovine placenta (Ward et al. 2002). Because fetal cortisol regulates the binucleate cell population, it possibly has certain implications for PL production in sheep. Similarly, in cows, it is likely that a fetal cortisol surge triggers the regression of the binucleate cell population and leads to the decrement of bPL production prior to parturition. The expression of bPL lasts to the end of gestation; the bPL message is still detectable in cotyledonary tissue collected immediately after calving (K. Ushizawa et al., unpubl. data, 2005). These results indicate that the commencement and cessation of bPL production are strictly regulated by both spatial and temporal situations of trophoblast differentiation. Bovine trophoblasts originate from the trophectoderm of the blastocyst and form three kinds of cell types: mononucleate, binucleate and trinucleate trophoblasts. Mononucleate trophoblasts are thought to be precursors for binucleate cells, even though they

play critical roles at a specic stage of gestation. Interferon- is expressed by the mononucleate trophoblasts just prior to feto-maternal contact (Imakawa et al. 1987). Binucleate cells display both migratory and endocrine functions during placental development (Wooding 1982). Recently, we established a new bovine trophoblast cell line (BT-1) for an in vitro model of trophoblast differentiation (Shimada et al. 2001). BT-1 cells proliferate without feeder cells in a collagencoated culture vessel. Under these conditions, the cells express interferon- and bPAG transcripts, but they express only negligible amounts of bPL. However, once they have differentiated into binucleate cells on collagen gel, but not on the collagen lm, these binucleate cells have features that are characteristic of those in vivo, including increased nuclear DNA content and expression of bPL. These results strongly suggest that the expression of bPL is closely related to trophoblast differentiation. bPL is also a functional determinant in trophoblast differentiation in rodents.

EXPRESSION PROFILE
Trophoblasts commence expression of bPL at the time of binucleate cell formation. The binucleate cell forms a trinucleate cell by fusing with endometrial epithelial cells and the trinucleate cells transfer the contents of secretory granules into maternal circulation (Wooding 1982). In the maternal circulation, bPL is detected in peripheral plasma following day 60 of gestation (Patel et al. 1996). Thereafter, plasma bPL concentrations increase gradually (up to 0.6 ng/mL) by day 200 of gestation. Plasma bPL concentrations rapidly double between day 200 and 220 (up to 1.3 ng/mL). The concentrations stabilize at this plateau level up to parturition. After calving, plasma bPL concentrations decline quickly on day 1 post partum. The plasma levels of bPL are comparable to the quantity of bPL transcripts in the placental tissue. Patel et al. (2004) reported that the transcription level of bPL in placentomes increased with the progression of gestation, and was still maintained at parturition. Changes in the plasma bPL concentration during gestation are relatively minor and more gradual than those of placental steroids (Takahashi et al. 1997; Patel et al. 1999) and bPAG (Patel et al. 1995). Plasma levels of placental products are regulated by the overall rate of biosynthesis at the source, utilization at the target and clearance from the circulation. The half-life of recombinant bPL derived from E. coli was estimated to be approximately 7.5 min (Byatt et al. 1992b). Although the

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half-life of native bPL synthesized by the placenta could possibly be longer than that of recombinant bPL because it is glycosylated, peripheral plasma bPL concentrations rapidly decrease 1 day after calving. Therefore, the short half-life of bPL is one of the main factors behind the gradual increment in plasma level. However, plasma levels of bPAG dramatically increase throughout gestation. Plasma bPAG is rst detected at approximately 3 weeks of gestation, at a concentration of 35 ng/mL. After that, its concentration increases dramatically and peaks at calving, with a concentration of more than 1000 ng/mL. The half-life of bPAG1 is estimated to be more than 8 days, because it is highly glycosylated, and plasma bPAG remains detectable for several weeks post partum (Green et al. 2005). Therefore, the longer half-life of bPAG is conducive to producing a particular plasma prole with cumulative increases during gestation and a persistent hangover after calving. bPL is also detected in the fetal circulation (Byatt et al. 1987; Takahashi et al. 2000). The concentration of bPL in fetal plasma is more than 10-fold greater than that in the maternal circulation. The concentration of bPL in fetal plasma declines with the progress of gestation. However, it is always greater than that in the maternal circulation. The different concentrations of bPL in the fetal and maternal plasma indicate that bPL primarily targets fetal tissues rather than those of the dam. Maternal plasma concentrations of estrogens and bPAG derived from the placenta are higher in twin than in singleton pregnancies (Patel et al. 1995; Takahashi et al. 1997; Patel et al. 1999). Several studies have reported a positive correlation between calf birth weight and maternal peripheral estrone sulfate concentrations (Takahashi et al. 1997; Zhang et al. 1999). Heavier calves, and increased total calf weight in twin pregnancies imply large placental dimensions and physiological output from the placenta. However, there is no signicant difference in maternal plasma concentrations of bPL between singleton and twin pregnancies over gestation, although plasma concentrations of estradiol, estrone sulfate and bPAG are higher in twin pregnancies. It is probable that a larger amount of bPL is produced in twin pregnancies; however, the bPL may be taken up and utilized by the twin fetuses, resulting in the same levels as found in maternal circulation in singleton pregnancies. These ndings support the hypothesis that the target tissue of bPL is in the fetal compartment. However, the actual mechanism(s) by which bPL acts should be further claried.

PHYSIOLOGICAL ROLES
The biological activities of PL have been observed principally in rodent species. In rodent species, PRL receptor ligands play a critical role in maintaining the corpus luteum (CL) in pregnancy. In early pregnancy, diurnal and nocturnal surges of PRL produced by the maternal pituitary act as a major luteotropic stimulus to form the functional CL in pregnancy. After midpregnancy, these twice-per-day surges are inhibited by PL-I, and PRL secretion remains at its lowest level until shortly before parturition (Grattan & Averill 1990; Tomogane et al. 1992, 1993). PL-I takes over from pituitary PRL in mid-pregnancy, and PL-II takes over from PL-I in late pregnancy. Rodent PL-I are an initial trigger to stimulate pancreatic islet B-cell function in mid-pregnancy. After PL-I secretions cease, PL-II takes over this role (Brelje et al. 1993; Kawai & Kishi 1997). In late pregnancy, pancreatic B-cells respond to PL-II secreting insulin, although the cells are no longer stimulated for proliferation (Kawai & Kishi 1999). Evidence suggests physiological roles for rodent PL in the maintenance of gestation, fetal growth, mammogenesis and maternal adaptation in pregnancy. For further information about the role of rodent placental PRL family protein during pregnancy, see the review by Soares et al. (2006) in this issue. However, physiological roles of PL found in rodents may not apply in ruminants. I will now review and discuss the role of PL, focusing on bovine PL.

Luteal function
Ruminant PL has been inferred to be potentially luteotropic because oPL acts as a luteotropin when administrated to pseudopregnant rats (Chan et al. 1980). Lucy et al. (1994) reported that recombinant bPL increased the size of the CL, increased plasma progesterone concentration and bound to the luteal microsomal fraction in heifers, although oPL has no effect on progesterone secretion in the ewe (Waters et al. 1985). These ndings suggest the presence of a PL-mediated signaling system in bovine CL as well as in rodents. In rodents, the luteotropic effect of PL occurs via the PRL receptor. However, in cows, neither GH nor PRL are able to compete for binding of bPL to CL, although the PRL receptor is expressed in bovine CL (Lucy et al. 1994). These results suggest that bovine CL express a unique receptor for bPL, which is distinct from both the GH receptor and PRL receptor, and that bPL has a particular role associated with CL function during pregnancy.

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Fetal growth and pregnancy-associated maternal adaptation

It has long been thought that PL is a factor involved in the partitioning of nutrients to maintain nutritional supply for fetal development. Rasby et al. (1990) studied the effect of nutrition and body reserves on fetal development, and measured the concentrations of nutrients and PL in maternal plasma in cows. In that study, the authors measured these parameters in pregnant cows that were thin and those with moderate body condition. There was no signicant difference in fetal growth between the two groups. Interestingly, in thin cows, uterine weights were less, but both chorioallantoic and cotyledonary weights were greater than those in cows with moderate body condition. Total fructose concentration in allantoic uid was reduced in thin cows. Additionally, maternal plasma bPL concentrations were higher in thin cows. The greater allantoic and cotyledonary weights suggest compensatory mechanisms to increase the amount of nutrients reaching the feto-placental compartment in thin cows. Because concentrations of allantoic fructose, the major energy source in the placenta, are less in thin cows, a greater bPL concentration may be related to the increased availability of nutrients in the fetal unit. These results are intriguing because they suggest a role for bPL in compensating for the debasement of nutritional conditions. Leibovich et al. (2000) reported increased oPL production in the placenta, heavier birth weight of newborns and increased milk yield in ewes that were immunized against oPL. In immunized ewes, secreted oPL is immediately neutralized by its own antibody, but local oPL production is activated, resulting in a greater concentration of oPL in the fetoplacental compartment.

depending on the situation. Byatt et al. (1997) examined the effect of exogenously administered bPL on milk yield in a dairy heifer induced lactation model. The milk yield of heifers treated with bPL was 22% higher than the yield of the control group. In this model, recombinant bGH increased milk yield in both bPL-treated and control heifers, and stimulated a greater increase in the yield for heifers treated with bPL. In lactating dairy cows, exogenous administration of bPL increased milk yield, although bPL was less potent than bGH (Byatt et al. 1992a). Administration of either bPL or bGH decreases blood concentrations of urea nitrogen, but increases serum concentrations of insulin-like growth factor-I. Plasma concentrations of nonesteried fatty acids and glucose were increased by bGH, but PL had little or no effect on lipolysis. Dry matter intake was increased by bPL but not by bGH. The effect of bPL in lactating dairy cows indicates that bPL is a potent agonist for increasing milk yield without altering lipolysis and insulin sensitivity. However, there is no denying that the galactopoietic effect of bPL is probably simply exerted via increased dry matter intake.

Placental angiogenesis
Although there is little evidence to suggest angiogenic activity for bPL or its derivative peptide, the hypothesis that bovine PRL family proteins are involved in the regulation of placental angiogenesis is plausible (Corbacho et al. 2002). Rat PRL can be cleaved by cathepsin D between amino acid residues Y145 and L146, and between W148 and S149, resulting in two polypeptides (16K and 6K) and a tripeptide (L-V-W) (Andries et al. 1992; Baldocchi et al. 1993). Among these peptides the 16K fragment retains lactogenic activity (Clapp et al. 1988). Following proteolytic cleavage, the resulting 16K PRL acquires a new bioactivity that is quite distinct from that of the parent molecule: it markedly inhibits angiogenesis (Struman et al. 1999). A recent report (Tabruyn et al. 2005) suggests that the potency of 16K PRL for inhibiting angiogenesis is related to its ability to induce endothelial cell cycle arrest. The Nterminus 16K rat PL fragment, which is generated by genetic engineering, also has inhibitory effects on angiogenesis. These effects are comparable to those of 16K PRL, although there is no evidence that 16K PL naturally occurs in vivo. However, no study has yet found that the 16K fragment of either bPRL or bPL modulates angiogenesis in bovine tissues. Also, the patterns of natural occurrence of the fragment in bovines are not known. Therefore, it is likely that the

Mammogenesis and lactogenesis

Lactogenic hormones are required for full lobuloalveolar growth in goat mammary glands, and ovarian steroids are needed for ductal growth (Cowie et al. 1966). In dairy heifers, mammogenesis is not inhibited by CB 154 administrated in the latter half of gestation (Schams et al. 1984). This result suggests that bPL is a potential substitute for pituitary PRL. Bovine PL has also been reported to have mitogenic activity in mammary tissue (Byatt et al. 1994). Potency comparable to that of mammary mitogen is not found in bPRL, although bPRL is more potent for the induction of milk synthesis. It is intriguing that exogenously administrated bPL may or may not increase milk yield,

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peptide derived from bPL has effects on angiogenesis in bovines.

CONCLUDING REMARKS
Most studies on PL have been carried out in rats and mice. Although there have been many studies on the physiological roles of PL in rodents, it is sometimes difcult to translate these ndings to ruminants. In ruminants, research has been carried out mainly using sheep and goats. Bovine placenta and bPL have characteristics that are different from those of ovine and caprine species, whereas the histological architecture of the placenta, molecular structure of PL and plasma PL proles are closely related in sheep and goats. Therefore, study of bPL in bovines is more difcult. According to research to date, bPL is involved in the regulation of ovarian function, mammogenesis, fetal growth and pregnancy-associated maternal adaptation. However, further efforts are needed for the study of bPL biology.

ACKNOWLEDGMENTS
I express profound thanks to Dr Kazuyoshi Hashizume, the last head of the Reproductive Biology and Technology Laboratory, for supervising the research on bPL. Thanks also to Dr Kei Imai and Mrs Kanako Kaneyama for helpful assistance in general, Drs Haruo Nakano and Arata Shimada for assistance with generation and characterization of BT-1 cells, Dr Osamu Yamada and Mrs Hiroko Nakano for assistance with immunohistochemistry and in situ hybridization, Drs Keiichio Kizaki and Osman V. Patel for assistance with gene expression analyses, and Drs Koichi Ushizawa and Misa Hosoe for general discussion and help in preparation of the manuscript. Research from our laboratory is supported by Grants-in-Aid from the Ministry of Agriculture, Forestry and Fisheries, the Basic Science for Innovative Bioscience program, the Organized Research Combination System and the Japan Society for the Promotion of Science.

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