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

PLACENTAL LACTOGENT. TAKAHASHI

Animal Science Journal (2006) 77, 10–17

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. Purified 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 first 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 first identified 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 identified earlier (Buttle & Forsyth 1976). Shortly after the discovery of bPL, bPL protein was purified 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 profile 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.

© 2006 Japanese Society of Animal Science

bPL has a consensus N-glycosylation site and many potential sites for Oglycosylation. 1991). which is present at a 2300-fold lower concentration than hGH. has been reported (Byatt et al. Among these members of the bovine placental PRL family. In SDS-PAGE under reducing conditions. 1990). 1988). Takahashi et al. 1991). The bPL secreted from the placenta seems to be heterogenous. bPL isoforms with the same molecular size and different pI values were also found to be present in placental tissues (Byatt et al. 1986. It is likely that new members of the PRL family have been generated by gene duplication from PRL (Wallis 1992). 1989). Carbohydrate chains appear to delay the biological clearance of proteins to maintain availability at the target tissue. where carbohydrate chains are added. whereas recombinant bPL produced in Escherichia coli. 1986. is a suitable tool for assaying bPL in both plasma and explant culture medium (Schellenberg & Friesen 1982. Kessler and Schuler (1991) reported the presence of truncated bPL transcripts comprising 13% of total bPL mRNA in mid-pregnancy placenta. RECEPTOR-BINDING CHARACTERISTICS Binding to the PRL receptor is one of the principal biochemical characteristics of bPL. 2001). Recombinant bPL migrates according to its real molecular weight under non-reducing conditions rather than under reduced conditions. with a 36-amino acid signal peptide (Schuler et al. The amino acid residues. Murthy et al. The lactogenic activity of bPL is almost equipotent to that of highly purified ovine PRL (Schellenberg & Friesen 1982). as measured by gel filtration chromatography in the presence of a denaturant. 1993) in addition to lactogenic ones. Additionally. 1990). 10–17 © 2006 Japanese Society of Animal Science . human PL (hPL) has an affinity to human GH (hGH) binding protein. 1982. bPL and bGH co-locate on chromosome 23 (Dietz et al. and the difference remains after enzymatic deglycosylation (Byatt et al. This speculation is supported by the evidence that bPRL. and its amino acid sequence has approximately 20% identity with that of bGH (Schuler et al.BOVINE PLACENTAL LACTOGEN 11 STRUCTURE OF BOVINE PLACENTAL LACTOGEN Early bPL purification 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. 1982. bPL is the only member of the classical (lactogenic) group. Molecular cloning studies using cDNA encoding bPL predict a prepro-bPL of 236 amino acids. However. which is not glycosylated. 1998). 1992). The discrepancies in past estimates of the molecular size of bPL are believed to be a result of the lower purification yield of the material and the differences in the procedures for molecular size estimation. 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 purified materials (Eakle et al. Arima & Bremel 1983). to our knowledge. Therefore. Therefore. although the amino acid sequence of hPL has 85% identity with that of hGH (Lowman et al. see Ushizawa & Hashizume 2006 in this issue). 1991). 1988). 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. the existence of multiple isoforms of bPL is a result of at least two distinct causes. 1990). The deduced molecular weight of deglycosylated bPL is approximately 22 000. In primates. 1977). Two-dimensional gel electrophoresis of intact bPL reveals molecules with two different molecular weights (29 000 and 32 000). Soares et al. The bPL amino acid sequence has 51% identity with bPRL. Interestingly. for assaying lactogenic hormones. Ovine PL (oPL) also binds with high affinity to primate and rodent GH receptors (Ogren & Talamantes 1988. 1986. However. 1998). Staten et al. bPL also has somatogenic properties (Ogren & Talamantes 1988. migrated with a molecular weight of 26 000 (Byatt et al. and 22% identity with both human PRL and bovine growth hormone (bGH). coli-derived bPL migrates with an apparent molecular weight of 22 000 (Byatt et al. it may have evolved from the ancestral gene of the PRL lineage (Soares et al. native bPL secreted by the placenta migrated with an apparent molecular weight of 32 000. E. This curious migration behavior in SDSPAGE may be associated with the amino acid sequence and the 3-D structure of bPL. The presence of bPL isoforms. This appears to be a result of multiple glycosylation patterns during post-translational modification. which differ from the major form with respect to both molecular size and electrical charge. under nonreducing conditions. Several new members of the bovine PRL gene family other than bPL have been reported (for review. or binding domain of ruminant PL associated with binding to the GH Animal Science Journal (2006) 77. Colosi et al. Because bPL has structural and functional similarities to bPRL. the Nb2 lymphoma cell bioassay.

Patel et al. Although the © 2006 Japanese Society of Animal Science Animal Science Journal (2006) 77.12 T. 10–17 . Changes in the plasma bPL concentration during gestation are relatively minor and more gradual than those of placental steroids (Takahashi et al. Plasma levels of placental products are regulated by the overall rate of biosynthesis at the source. Under these conditions. The plasma levels of bPL are comparable to the quantity of bPL transcripts in the placental tissue. Goffin et al. After calving. ruminant PL antagonize the binding of oGH to the oGH receptor and occupy the receptor without inducing the homodimerization of receptors. 1992b). Ushizawa et al. 2002). 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). The concentrations stabilize at this plateau level up to parturition. unpubl. These results strongly suggest that the expression of bPL is closely related to trophoblast differentiation. Recently. Additionally. At approximately day 60 of gestation. Plasma bPL concentrations rapidly double between day 200 and 220 (up to 1. 2002). ruminant PL are not able to activate ovine GH receptor-mediated biological actions or act as antagonists.3 ng/mL). including increased nuclear DNA content and expression of bPL. 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. Bovine trophoblasts originate from the trophectoderm of the blastocyst and form three kinds of cell types: mononucleate. the bPL message is still detectable in cotyledonary tissue collected immediately after calving (K. bPL is detected in peripheral plasma following day 60 of gestation (Patel et al. 2001). Patel et al. Because fetal cortisol regulates the binucleate cell population. Yamada et al. Because ruminant PL binds to the ovine GH (oGH) receptor at a ratio of 1:1. SOURCE OF EXPRESSION The bPL mRNA is transcribed in trophoblast binucleate cells (Yamada et al. data. utilization at the target and clearance from the circulation. 2002). (1996) suggest that the binding of ruminant PL to GH receptors does not require a specific residue/domain for hormone– receptor interactions. 1995). 2002). it possibly has certain implications for PL production in sheep. In the maternal circulation. the cells express interferon-τ and bPAG transcripts. plasma bPL concentrations increase gradually (up to 0. Similarly. 2005). binucleate and trinucleate trophoblasts. 1999). Mononucleate trophoblasts are thought to be precursors for binucleate cells. However. even though they play critical roles at a specific stage of gestation. but they express only negligible amounts of bPL. in cows. 1996). 2002). these binucleate cells have features that are characteristic of those in vivo. Similarly. bPL is also a functional determinant in trophoblast differentiation in rodents. (2004) reported that the transcription level of bPL in placentomes increased with the progression of gestation. 1987). TAKAHASHI receptor. It has been reported that the number of binucleate cells expressing PL decreases during late gestation in ovine placenta (Ward et al. remain unclear. most of the binucleate cells (>95%) express bPL protein. 1979. coli was estimated to be approximately 7.5 min (Byatt et al. BT-1 cells proliferate without feeder cells in a collagencoated culture vessel. we established a new bovine trophoblast cell line (BT-1) for an in vitro model of trophoblast differentiation (Shimada et al. plasma bPL concentrations decline quickly on day 1 post partum. 1997. and was still maintained at parturition. whereas no expression is detected in mononucleate cells (Yamada et al. 1999) and bPAG (Patel et al. but not on the collagen film.. The expression of bPL lasts to the end of gestation. These results indicate that the commencement and cessation of bPL production are strictly regulated by both spatial and temporal situations of trophoblast differentiation. 2002) and synthesized bPL protein is stored in membrane-bound secretory granules in these cells (Wooding 1982). Interferon-τ is expressed by the mononucleate trophoblasts just prior to feto-maternal contact (Imakawa et al. The half-life of recombinant bPL derived from E. at or shortly after the appearance of binucleate cells in the trophoblast. EXPRESSION PROFILE Trophoblasts commence expression of bPL at the time of binucleate cell formation. Binucleate cells display both migratory and endocrine functions during placental development (Wooding 1982). Thereafter. the expression of bPL co-localizes with that of pregnancy-associated glycoprotein (bPAG)-1 in the same binucleate trophoblast (Yamada et al. The mRNA encoding bPL is first detectable with in situ hybridization in trophoblast binucleate cells at approximately day 20 of gestation (Yamada et al. although they can activate GH receptor-mediated biological activities in humans and rabbits (Herman et al. bPL protein is also detectable on the same day (Flint et al. However. once they have differentiated into binucleate cells on collagen gel.6 ng/mL) by day 200 of gestation.

1995. In rodents. the luteotropic effect of PL occurs via the PRL receptor. mammogenesis and maternal adaptation in pregnancy. Plasma bPAG is first detected at approximately 3 weeks of gestation. these twice-per-day surges are inhibited by PL-I. In rodent species. However. and PL-II takes over from PL-I in late pregnancy. which is distinct from both the GH receptor and PRL receptor. Takahashi et al. 1999). PHYSIOLOGICAL ROLES The biological activities of PL have been observed principally in rodent species. 2005). 10–17 © 2006 Japanese Society of Animal Science . It is probable that a larger amount of bPL is produced in twin pregnancies. Rodent PL-I are an initial trigger to stimulate pancreatic islet B-cell function in mid-pregnancy. neither GH nor PRL are able to compete for binding of bPL to CL. Tomogane et al. These findings support the hypothesis that the target tissue of bPL is in the fetal compartment. 1999). In late pregnancy. the longer half-life of bPAG is conducive to producing a particular plasma profile with cumulative increases during gestation and a persistent hangover after calving. Heavier calves. After that. However. However. However. The different concentrations of bPL in the fetal and maternal plasma indicate that bPL primarily targets fetal tissues rather than those of the dam. 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. although oPL has no effect on progesterone secretion in the ewe (Waters et al. 1997. PL-I takes over from pituitary PRL in mid-pregnancy. The concentration of bPL in fetal plasma declines with the progress of gestation. 1993). Kawai & Kishi 1997). the short half-life of bPL is one of the main factors behind the gradual increment in plasma level. resulting in the same levels as found in maternal circulation in singleton pregnancies. PRL receptor ligands play a critical role in maintaining the corpus luteum (CL) in pregnancy. 1987. PL-II takes over this role (Brelje et al. Zhang et al. at a concentration of 3–5 ng/mL. The concentration of bPL in fetal plasma is more than 10-fold greater than that in the maternal circulation. Takahashi et al. focusing on bovine PL. pancreatic B-cells respond to PL-II secreting insulin. with a concentration of more than 1000 ng/mL. 1993. 2000). and that bPL has a particular role associated with CL function during pregnancy. I will now review and discuss the role of PL. diurnal and nocturnal surges of PRL produced by the maternal pituitary act as a major luteotropic stimulus to form the functional CL in pregnancy. it is always greater than that in the maternal circulation. physiological roles of PL found in rodents may not apply in ruminants. These findings suggest the presence of a PL-mediated signaling system in bovine CL as well as in rodents. plasma levels of bPAG dramatically increase throughout gestation. and PRL secretion remains at its lowest level until shortly before parturition (Grattan & Averill 1990. However. Animal Science Journal (2006) 77. in cows. although the cells are no longer stimulated for proliferation (Kawai & Kishi 1999). Evidence suggests physiological roles for rodent PL in the maintenance of gestation. Therefore. its concentration increases dramatically and peaks at calving. 1985). Several studies have reported a positive correlation between calf birth weight and maternal peripheral estrone sulfate concentrations (Takahashi et al. Therefore. Lucy et al. However. For further information about the role of rodent placental PRL family protein during pregnancy. although plasma concentrations of estradiol. estrone sulfate and bPAG are higher in twin pregnancies. 1980). the actual mechanism(s) by which bPL acts should be further clarified. peripheral plasma bPL concentrations rapidly decrease 1 day after calving. increased plasma progesterone concentration and bound to the luteal microsomal fraction in heifers. see the review by Soares et al. and plasma bPAG remains detectable for several weeks post partum (Green et al. 1992. (1994) reported that recombinant bPL increased the size of the CL. the bPL may be taken up and utilized by the twin fetuses. however. The half-life of bPAG1 is estimated to be more than 8 days. bPL is also detected in the fetal circulation (Byatt et al. These results suggest that bovine CL express a unique receptor for bPL. 1997. although the PRL receptor is expressed in bovine CL (Lucy et al. (2006) in this issue. 1994). After midpregnancy. there is no significant difference in maternal plasma concentrations of bPL between singleton and twin pregnancies over gestation. and increased total calf weight in twin pregnancies imply large placental dimensions and physiological output from the placenta. fetal growth. because it is highly glycosylated. After PL-I secretions cease. Maternal plasma concentrations of estrogens and bPAG derived from the placenta are higher in twin than in singleton pregnancies (Patel et al.BOVINE PLACENTAL LACTOGEN 13 half-life of native bPL synthesized by the placenta could possibly be longer than that of recombinant bPL because it is glycosylated. In early pregnancy. Patel et al.

In that study. Following proteolytic cleavage. secreted oPL is immediately neutralized by its own antibody. 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. Also. the hypothesis that bovine PRL family proteins are involved in the regulation of placental angiogenesis is plausible (Corbacho et al. These results are intriguing because they suggest a role for bPL in compensating for the debasement of nutritional conditions. Potency comparable to that of mammary mitogen is not found in bPRL. Total fructose concentration in allantoic fluid was reduced in thin cows. mammogenesis is not inhibited by CB 154 administrated in the latter half of gestation (Schams et al. Bovine PL has also been reported to have mitogenic activity in mammary tissue (Byatt et al. 2002). recombinant bGH increased milk yield in both bPL-treated and control heifers. This result suggests that bPL is a potential substitute for pituitary PRL. A recent report (Tabruyn et al. Leibovich et al. Plasma concentrations of nonesterified fatty acids and glucose were increased by bGH. Placental angiogenesis Although there is little evidence to suggest angiogenic activity for bPL or its derivative peptide. However. resulting in two polypeptides (16K and 6K) and a tripeptide (L-V-W) (Andries et al. resulting in a greater concentration of oPL in the fetoplacental compartment. uterine weights were less. (1990) studied the effect of nutrition and body reserves on fetal development. 1992a). In immunized ewes. In dairy heifers. Rat PRL can be cleaved by cathepsin D between amino acid residues Y145 and L146. and ovarian steroids are needed for ductal growth (Cowie et al. exogenous administration of bPL increased milk yield. Because concentrations of allantoic fructose. 10–17 . However. 1988). but both chorioallantoic and cotyledonary weights were greater than those in cows with moderate body condition. Byatt et al. 1999). there is no denying that the galactopoietic effect of bPL is probably simply exerted via increased dry matter intake. although bPL was less potent than bGH (Byatt et al. 1993). Rasby et al. Dry matter intake was increased by bPL but not by bGH. In this model. © 2006 Japanese Society of Animal Science Animal Science Journal (2006) 77. 1994). 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. It is intriguing that exogenously administrated bPL may or may not increase milk yield. Interestingly. Baldocchi et al. Administration of either bPL or bGH decreases blood concentrations of urea nitrogen. 1992. (2000) reported increased oPL production in the placenta. Additionally. no study has yet found that the 16K fragment of either bPRL or bPL modulates angiogenesis in bovine tissues. The Nterminus 16K rat PL fragment. but local oPL production is activated. depending on the situation. There was no significant difference in fetal growth between the two groups. TAKAHASHI 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. 1984). and stimulated a greater increase in the yield for heifers treated with bPL. In lactating dairy cows. 1966). Therefore.14 T. heavier birth weight of newborns and increased milk yield in ewes that were immunized against oPL. The milk yield of heifers treated with bPL was 22% higher than the yield of the control group. and measured the concentrations of nutrients and PL in maternal plasma in cows. the patterns of natural occurrence of the fragment in bovines are not known. are less in thin cows. and between W148 and S149. These effects are comparable to those of 16K PRL. but PL had little or no effect on lipolysis. in thin cows. but increases serum concentrations of insulin-like growth factor-I. the major energy source in the placenta. although there is no evidence that 16K PL naturally occurs in vivo. Among these peptides the 16K fragment retains lactogenic activity (Clapp et al. The greater allantoic and cotyledonary weights suggest compensatory mechanisms to increase the amount of nutrients reaching the feto-placental compartment in thin cows. the authors measured these parameters in pregnant cows that were thin and those with moderate body condition. although bPRL is more potent for the induction of milk synthesis. 2005) suggests that the potency of 16K PRL for inhibiting angiogenesis is related to its ability to induce endothelial cell cycle arrest. maternal plasma bPL concentrations were higher in thin cows. it is likely that the Mammogenesis and lactogenesis Lactogenic hormones are required for full lobuloalveolar growth in goat mammary glands. a greater bPL concentration may be related to the increased availability of nutrients in the fetal unit. which is generated by genetic engineering. (1997) examined the effect of exogenously administered bPL on milk yield in a dairy heifer induced lactation model. also has inhibitory effects on angiogenesis.

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