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Endocrinology Vol. 138, No. 1 149-155
Copyright © 1997 by The Endocrine Society

ARTICLES

Proliferin Transport and Binding in the Mouse Fetus1

Dowdy Jackson 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 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
 
Proliferin (PLF), a member of the PRL/GH family secreted by the placenta, can be detected in both the maternal and fetal compartments. We now show that PLF immunoreactivity can be detected in association with the yolk sac, consistent with the transport of PLF across this structure into the amniotic fluid. Furthermore, PLF is transported across the extraembryonic membranes in isolated conceptuses that are placed in culture, and specific binding sites for PLF are detected in these embryos. The major binding sites for PLF in the cultured conceptus correspond to sites at which endogenous PLF localizes in the fetus, including developing vertebral and vascular structures. Similar binding patterns were also detected for PLF that was incubated with fetal sections. Competition and comparative binding studies indicate that the insulin-like growth factor II/mannose 6-phosphate receptor is involved in PLF binding to specific cells in the fetus. These results suggest that in addition to the effects of PLF in the placenta on neovascularization and in the maternal uterus on cell proliferation, PLF may also act at specific sites in the developing fetus.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PROLIFERIN (PLF) is a member of the PRL/GH family that is synthesized in vivo specifically in placental trophoblast giant cells (1, 2, 3). We recently demonstrated that PLF is angiogenic and represents the predominant stimulatory activity secreted by the midpregnancy mouse placenta in an endothelial cell migration assay (4). Furthermore, PLF binds to capillary endothelial cells in the placenta (4) and, thus, is predicted to act as a paracrine regulator of placental blood vessel development. The ability of PLF to bind to endothelial cells and stimulate their migration in cell cultures and neovascularization in vivo depends on an association of this hormone with the insulin-like growth factor II/mannose 6-phosphate (IGF-II/M6P) receptor (5). The interaction of PLF with the IGF-II/M6P receptor is mediated at least in part by the PLF carbohydrate moiety, as M6P competes with PLF for receptor binding (6), and deglycosylated PLF is inactive on endothelial cells (5). PLF is also secreted into the maternal circulation at high levels (7) and has effects on maternal tissues. Nilsen-Hamilton and colleagues have found that this hormone can bind to a specific, high affinity receptor present in the uterus that is distinct from the IGF-II/M6P receptor, and that binding to these uterine cells results in the stimulation of DNA synthesis (8).

Previous studies have demonstrated that PLF also enters the amniotic fluid and, thus, may have direct effects on the fetus (3). In contrast, PLF-related protein, another member of this hormone family that is a potent antiangiogenic factor (4), does not enter the fetal compartment (9). We, therefore, sought to establish a system in which specific transport of PLF into the fetal compartment can be examined and to determine whether transported PLF binds to specific sites in the mouse fetus. The identification of specific binding sites provides a means of identifying possible targets for PLF in regulating fetal development.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and animal care
Pregnant Swiss-Webster mice at defined times of gestation were obtained from Harlan Breeding Laboratories (Indianapolis, IN) and maintained on 14-h light, 10-h dark cycles, with food and water freely available. All procedures were approved by the institutional animal care and use committee.

Iodinations and binding assays
Iodination of PLF was carried out using Iodogen (Pierce Chemical Co., Rockford, IL), and IGF-II (Gro-Pep, Adelaide, Australia) was iodinated with chloramine-T. Radiolabeled protein was separated from free 125I by gel filtration chromatography. Peak fractions were collected, concentrated by centrifugation in a Centricon (Amicon, Danvers, MA), and stored at 4 C until used. Five- to 20-µm sections were generated from frozen mouse fetuses on a cryostat and mounted on gelatin-coated slides. Nonspecific binding sites were blocked by incubation of the sections in 50 mM Tris-HCl (pH 7.6), 2 mM EGTA, 0.1 mM phenylmethylsulfonylfluoride, 140 mM NaCl, and 0.1% BSA for 15 min at room temperature. After rinsing twice in cold PBS, sections were incubated in 50 mM Tris-HCl (pH 7.6), 2 mM EGTA, 0.1 mM phenylmethylsulfonylfluoride, 5 mM MgCl2, 5 mM CaCl2, 5 mM MnCl2, and either [125I]PLF or [125I]IGF-II for 24–28 h at 4 C in a humidified chamber. The sections were then rinsed with PBS, treated for 15 min at 4 C with cross-linking reagent (2 mM BS3; Pierce) to fix bound hormone, rinsed again with PBS, and coated with Kodak NTB-2 photographic emulsion (Eastman Kodak, Rochester, NY). Endothelial cells in certain sections were identified by the ability to bind the B4 lectin from Bandeiraea simplicifolia (Sigma).

Fetal transport and accumulation
Intact mouse conceptuses, including the placenta and extra-embryonic membranes, but with the uterine tissue removed, were isolated and immediately placed into DMEM, supplemented with amino acids (to final concentrations of 22 µM arginine, 2 mM glutamine, 48 µM histidine, 8 µM lysine, 17 µM methionine, 65 µM proline, and 10 µM tryptophan), penicillin/streptomycin, and 50% mouse serum, that had been warmed to 37 C in a CO2 (5%) incubator; no differences in transport were detected using nonpregnant compared to pregnant mouse serum. The maintenance of a steady heart beat was the criterion used to establish viability. Iodinated PLF (105 to 5 x 105 cpm/ml) was added to the medium for 30–60 min. Conceptuses were then removed and rapidly frozen in a dry ice-ethanol bath or in liquid nitrogen and sectioned on a cryostat. Sections were treated with cross-linking reagent as described above (either BS3 or disuccinimidyl suberate from Pierce), fixed with 5% paraformaldehyde, washed, dried, and coated with photographic emulsion (Kodak NTB-2). All binding studies were conducted with at least three conceptuses for each time point to verify that the binding patterns were reproducible.

Immunofluorescence
Fetuses from different days of gestation were rapidly frozen, and 10-µm sections were generated with a cryostat. Sections were placed onto gelatin-coated slides and incubated for 24 h at 4 C in a humidified chamber with a 700-fold dilution into PBS of a rabbit anti-PLF antiserum (7) or preimmune serum (both provided by Se-Jin Lee and Daniel Nathans). Samples were washed extensively with PBS and then incubated for 1 h at room temperature with fluorescein-conjugated goat antirabbit secondary antibody. The samples were again washed with PBS, and immunostaining was visualized by fluorescence microscopy.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Transport of PLF into the fetal compartment
In the rodent, the yolk sac is the site of macromolecular transport from the placenta to the fetus, as has been demonstrated for Ig (10), ferritin (11), and vitamin B12 in complex with a binding factor (12). As PLF is produced only in the placenta in vivo, but has been detected in the amniotic fluid (3), it seemed likely that this protein is capable of binding to and passing through the yolk sac membrane. Sections from a day 10 conceptus, the time of maximal PLF synthesis (2, 3), were, therefore, incubated with a polyclonal antiserum against PLF to determine whether this protein could be found in association with the yolk sac. Indeed, immunoreactive protein was detected both in the trophoblast giant cells, the site of PLF synthesis, and in the yolk sac (Fig. 1Go); no immunostaining was seen with preimmune serum (data not shown). The punctate pattern of immunoreactive protein in the yolk sac may represent endocytosed PLF that is concentrated in endosomes.



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  		Figure 1. Detection of immunoreactive PLF in the yolk sac. Sections from a mouse conceptus on day 10 of gestation were incubated with an antiserum against PLF. Immunofluorescence (bright regions) is seen as punctate staining throughout the yolk sac and in the PLF-expressing giant trophoblast cells.

 
If the immunoreactivity detected in the yolk sac corresponds to PLF protein in the process of being transported, then it may be possible to detect PLF transport in culture. Toward this goal, mouse conceptuses were isolated, and the fetus, extraembryonic membranes, and placenta were separated from the maternal decidual tissue and placed in medium supplemented with mouse serum and [125I]PLF protein. In these experiments, the fetus remained viable during the 30- to 60-min incubation period, as judged by the presence of a heartbeat. At the end of the incubation period, the fetus was rapidly frozen, sectioned, and exposed to photographic emulsion. As shown in Fig. 2Go, PLF protein entered the fetus and bound to a limited number of sites, most prominently the developing vertebrae.



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  		Figure 2. Transport and accumulation of PLF in the fetus. A mouse conceptus from day 16 of gestation was incubated with [125I]PLF for 60 min, then sectioned and coated with photographic emulsion. A, Brightfield photomicrograph of a region of the fetus including the developing vertebral column (see Fig. 3Go for the location and size of this region in the fetus). B, Darkfield photomicrograph showing PLF binding to developing vertebral structures (bright regions).

 
The entry and localization of PLF in the fetus appeared to be specific for this hormone, as parallel incubations of intact conceptuses with radioiodinated PLF-related protein, another placental-specific member of the PRL/GH family, resulted in no detectable bound protein in the fetus (data not shown). The nature of the transport apparatus for PLF is not known, but the addition of 10 mM M6P to the medium during the incubation period had no observable effect on PLF transport into the fetus. [For an input of 450,000 cpm [125I]PLF, fetal counts per min were 8,242 ± 534 and 9,160 ± 278 without and with M6P, respectively (n = 5 in each case).] As M6P can effectively block PLF binding to the IGF-II/M6P receptor (5, 6), transport across the yolk sac membrane may not involve an association of PLF with this receptor.

Localization of endogenous PLF in the fetus
As the binding of [125I]PLF to these developing vertebral structures was so pronounced, we thought that it might be possible to detect the accumulation of endogenous PLF protein (i.e. secreted from the placenta) at these structures as well. Fetal sections were, therefore, surveyed by indirect immunofluorescence with an antiserum against PLF, and by this approach, immunoreactive PLF protein was also found to be localized to these vertebral structures (Fig. 3Go). Incubation of the antiserum with excess purified PLF protein before application to the fetal sections resulted in the loss of immunofluorescence (data not shown). PLF immunoreactivity does not appear to be due to local synthesis at this site, because PLF messenger RNA was not detected in these vertebral structures either by in situ hybridization with a PLF complementary DNA probe or by a coupled reverse transcription-PCR with RNA isolated from these dissected structures (data not shown).



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  		Figure 3. Detection of endogenous PLF immunoreactivity in the developing vertebral structures in the fetus. Sections from a day 16 mouse fetus were incubated with an antiserum against PLF, and sites of PLF immunoreactivity were detected by immunofluorescence microscopy. A, Brightfield view of the fetal section. Box i identifies the region shown in Fig. 2Go; boxes ii and iii mark the regions shown in B and C, respectively. The widths of these regions in the fetus are approximately 2.2 mm (box i), 1.2 mm (box ii), and 0.9 mm (box iii), respectively. B and C, Immunofluorescence with an antiserum against PLF showing staining (bright regions) in developing vertebral structures. D, Higher magnification of the region shown in C.

 
Binding of PLF to fetal sections
The data in Figs. 2Go and 3Go were obtained with conceptuses from the later part of gestation, as it was technically more feasible to work with these larger conceptuses for the transport studies. However, PLF protein levels peak at midgestation, and distinct fetal targets may exist for this hormone at earlier stages of development. As the localization of radiolabeled PLF and endogenous immunoreactive PLF in the intact and sectioned fetuses, respectively, from late gestation was indistinguishable, we analyzed PLF binding to the midgestation fetus by incubation of [125I]PLF with tissue sections.

Fetal sections from day 10 of gestation bound PLF predominantly in the developing heart and in blood vessels around the dorsal artery (Fig. 4Go). The addition of excess unlabeled PLF eliminated binding to these structures, indicating that PLF binding to these sites was specific. On days 12, 16, and 18, binding to the heart and blood vessels was still detected, but the accumulation of PLF in the developing vertebrae and ribs became much more pronounced in the later stages of gestation (Fig. 5Go), as was seen in the previous experiments. Although PLF may be adhering to more than one cell type, in the developing ribs PLF was bound to endothelial cells lining blood vessels, as indicated by the staining of endothelial cells on adjacent sections with Bandeiraea simplicifolia lectin B4 (Fig. 6Go). M6P effectively competed with PLF for all of the major binding sites in the fetus, indicating that PLF is interacting with the IGF-II/M6P receptor (Figs. 5Go and 6Go). Incubation of additional fetal sections from days 12, 16, and 18 with radioiodinated IGF-II revealed a pattern of binding indistinguishable from that of PLF (compare Figs. 5Go and 7Go), consistent with an association of PLF with the IGF-II/M6P receptor.



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  		Figure 4. Binding sites for PLF in the midgestation embryo. Sections from a day 10 mouse embryo were incubated with [125I]PLF without (B) or with (C) excess unlabeled PLF (1 µg/ml) as competitor. A, Brightfield photomicrograph of the section, indicating the locations of the developing heart and dorsal artery. B and C, Darkfield photomicrographs in which PLF binding is seen as bright regions. The width of the embryonic section is approximately 3 mm.

 


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  		Figure 5. Binding site for PLF in the mouse fetus during the latter half of gestation. Sections from a day 12 (A and B), a day 16 (C and D), or a day 18 (E and F) mouse fetus were incubated with [125I]PLF without (A, C, and E) or with (B, D, and F) 10 mM M6P as a competitor. All panels are darkfield photomicrographs in which PLF binding is visualized as bright regions. Prominent regions of PLF binding are labeled. Note that M6P competes effectively for PLF binding. The widths of the embryonic sections are approximately 5 mm (day 12), 14 mm (day 16), and 24 mm (day 18), respectively.

 


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  		Figure 6. Interaction of PLF with IGF-II/M6P receptors on fetal endothelial cells. Day 18 mouse fetal sections were incubated with [125I]PLF, stained with the endothelial cell-specific lectin B4 from Bandeiraea simplicifolia, and then exposed to photographic emulsion. A, Brightfield view of a cross-section of a developing rib, with blood vessel endothelial cells identified by staining with the B4 lectin. B, Darkfield photomicrograph showing PLF binding to endothelial cells (bright regions). C, Darkfield view of an adjacent section after incubation with [125I]PLF and 10 mM M6P, demonstrating that M6P is an effective competitor for PLF-binding sites on these endothelial cells.

 


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  		Figure 7. IGF-II-binding sites in the mouse fetus. Sections from a day 12 (A and B), a day 16 (C and D), or a day 18 (E and F) mouse fetus were incubated with [125I]IGF-II without (A, C, and E) or with (B, D, and F) excess IGF-II (1 µg/ml) as competitor. All panels are darkfield photomicrographs in which IGF-II binding is visualized as bright regions. Prominent regions of IGF-II binding are labeled and correspond to sites of PLF binding (Fig. 5Go). The widths of the embryonic sections are approximately 5 mm (day 12), 14 mm (day 16), and 24 mm (day 18), respectively.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We have developed a system in which the specific transport of a placental protein into the fetal compartment can be monitored in a viable conceptus. PLF had previously been demonstrated to enter this compartment and accumulate in the amniotic fluid to levels approaching 1 µg/ml on day 10 of gestation (3). Endogenous PLF released from the placenta can be detected in association with the yolk sac, suggesting that the yolk sac membrane contains specific transporters that deliver PLF into the fetal compartment; specific receptors for yolk sac transport of Igs have previously been identified (13). It is possible that the punctate PLF immunoreactivity that we detected in the yolk sac represents PLF protein that has been internalized and concentrated in endosomes and that may be destined for transcytosis and release on the fetal side of the membrane. A similar punctate staining pattern is seen for the wingless protein, for example, in cells through which it is being transported (14, 15).

The addition of PLF to the medium in which an intact conceptus is cultured resulted in the passage of this protein into the fetus and the localization of radiolabeled protein to specific structures. In contrast, the placental hormone PLF-related protein is known not to enter the fetal compartment (9) and does not accumulate in the fetus in this conceptus culture system. Thus, PLF-related protein, unlike PLF, may not be transported across the extraembryonic membranes in this system, but we cannot exclude the possibility that radioiodination interfered with PLF-related protein transport or that PLF-related protein enters the fetus, but does not accumulate at any specific sites because of a lack of unoccupied receptors.

Upon passing through the extraembryonic membranes of the late gestation conceptus, PLF accumulates predominantly in the developing vertebral and rib structures. Although this assay will only identify structures with unoccupied receptors for PLF, these structures appear to represent physiologically relevant sites of PLF binding, as endogenous PLF immunoreactivity was detected at these sites as well. Radiolabeled PLF protein added to frozen fetal sections also localized to these structures, providing additional evidence that these sites represent bona fide targets of PLF protein and that iodinated protein retains the binding specificity of the unlabeled hormone. Furthermore, even though the levels of PLF decline late in gestation, the PLF concentration in maternal serum and amniotic fluid is approximately 100 ng/ml on days 16–18 (3), consistent with PLF still having a direct role in fetal development at this stage. The physiological effects of PLF binding in these regions are not yet known. Some of the targets are endothelial cells that would presumably be stimulated by PLF to migrate (4). As PLF can stimulate uterine cell division in the mother (8), PLF may also act as a mitogen on fetal targets.

The specific interactions of PLF with fetal cells that were detected involve an association of this hormone with the IGF-II/M6P receptor, based on the ability of M6P to block PLF binding to fetal tissues in thin sections. We have previously demonstrated that M6P blocks PLF-induced endothelial cell migration at concentrations at which it blocks binding of the radioiodinated hormone to the IGF-II/M6P receptor (5, 6). Interestingly, this sugar was unable to prevent the passage of PLF across the extraembryonic membranes, suggesting that either the IGF-II/M6P receptor is not limiting for PLF transport across the yolk sac or that transport occurs independently of this receptor. Additional evidence that PLF is binding to the IGF-II/M6P receptor in the fetus comes from a comparison of PLF- and IGF-II-binding sites as well as a comparison of PLF-binding sites to known sites of IGF-II/M6P receptor expression (16). As this receptor plays an essential role in mediating PLF-induced endothelial cell migration and neovascularization (5), it seems likely that PLF will also have direct effects on fetal cells expressing the IGF-II/M6P receptor on their surface. Therefore, some of the defects seen in the development of mice that lack a functional IGF-II/M6P receptor (17, 18) may reflect an inability of fetal cells to respond to PLF, although the expression of more than one type of receptor for PLF and the probable redundancy of signaling pathways may obscure an interpretation of PLF action in this genetic background. Targets for PLF in the fetus include endothelial cells, but other cell types, especially in the developing vertebrae, may also bind and respond to PLF. The ability of PLF to act on multiple cell types is evident from the demonstrated ability of this hormone to act as a mitogen in the uterus (8) and as a stimulator of migration for endothelial cells (4). The challenge now will be to determine what physiological effects are induced by PLF at each of the various fetal targets.


   Acknowledgments
 
We gratefully acknowledge the generosity of Se-Jin Lee and Daniel Nathans for providing purified PLF protein and antiserum, and the comments of Noël Bouck on this manuscript.


   Footnotes
 
1 This work was supported by NIH Grants HD-24518 (to D.L.) and HD-28048 (to the P30 Center in Reproductive Biology). Back

Received July 8, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Linzer DIH, Nathans D 1984 Nucleotide sequence of a growth-related mRNA encoding a member of the prolactin-growth hormone family. Proc Natl Acad Sci USA 81:4255–4259[Abstract/Free Full Text]
  2. Linzer DIH, Lee SJ, Ogren L, Talamantes F, Nathans D 1985 Identification of proliferin mRNA and protein in mouse placenta. Proc Natl Acad Sci USA 82:4356–4359[Abstract/Free Full Text]
  3. Lee SJ, Talamantes F, Wilder E, Linzer DIH, Nathans D 1988 Trophoblastic giant cells of the mouse placenta as the site of proliferin synthesis. Endocrinology 122:1761–1768[Abstract]
  4. Jackson D, Volpert OV, Bouck N, Linzer DIH 1994 Stimulation and inhibition of angiogenesis by placental proliferin and proliferin-related protein. Science 266:1581–1584[Abstract/Free Full Text]
  5. Volpert O, Jackson D, Bouck N, Linzer DIH 1996 Role of the insulin-like growth factor II/mannose 6-phosphate receptor in proliferin-induced angiogenesis. Endocrinology 137:3871–3876[Abstract]
  6. Lee SJ, Nathans D 1988 Proliferin secreted by cultured cells binds to mannose 6-phosphate receptors. J Biol Chem 263:3521–3527[Abstract/Free Full Text]
  7. Lee SJ, Nathans D 1987 Secretion of proliferin. Endocrinology 120:208–213[Abstract]
  8. Nelson JT, Rosenzweig N, Nilsen-Hamilton M 1995 Characterization of the mitogen-regulated protein (proliferin) receptor. Endocrinology 136:283–288[Abstract]
  9. Lopez MF, Ogren L, Linzer DIH, Talamantes F 1993 Pituitary-placental interaction during pregnancy: regulation of prolactin-like proteins. Endocr J (USA) 1:513–518
  10. Brambell FWR, Halliday R 1956 The route by which passive immunity is transmitted from mother to foetus in the rat. Proc R Soc Lond [Biol] 145:170–178
  11. Lambson RO 1966 An electron microscopic visualization of transport across rat visceral yolk sac. Am J Anat 118:21–52[CrossRef][Medline]
  12. Padykula HA, Deren JJ, Wilson TH 1966 Development of structure and function in the mammalian yolk sac. I. Developmental morphology and vitamin B12 uptake of the rat yolk sac. Dev Biol 13:311–348[CrossRef][Medline]
  13. Roberts DM, Guenthert M, Rodewald R 1990 Isolation and characterization of the Fc receptor from the fetal yolk sac of the rat. J Cell Biol 111:1867–1876[Abstract/Free Full Text]
  14. Gonzalez F, Swales L, Bejsovec A, Skaer H, Martinez-Arias A 1991 Secretion and movement of wingless protein in the epidermis of the Drosophila embryo. Mech Dev 35:43–54[CrossRef][Medline]
  15. Bejsovec A, Wieschaus E 1995 Signaling activities of the Drosophila wingless gene are separately mutable and appear to be transduced at the cell surface. Genetics 139:309–320[Abstract]
  16. Matzner U, Von Figura K, Pohlmann R 1992 Expression of the two mannose 6-phosphate receptors is spatially and temporally different during mouse embryogenesis. Development 114:965–972[Abstract]
  17. Wang ZQ, Fung MR, Barlow DP, Wagner EF 1994 Regulation of embryonic growth and lysosomal targeting by the imprinted Igf2/Mpr gene. Nature 372:464–467[CrossRef][Medline]
  18. Lau MHH, Stewart CEH, Liu Z, Bhatt H, Rotwein P, Stewart CL 1994 Loss of the imprinted IGF2/cation-independent mannose 6-phosphate receptor results in fetal overgrowth and perinatal lethality. Genes Dev 8:2953–2963[Abstract/Free Full Text]



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