The polypeptide hormone prolactin (PRL) has been implicated in the regulation of embryonic growth and development, but the control mechanisms involved in the effects of the hormone are poorly understood. Several investigators suggested that there may be a possible link between the effects of PRL and insulin-like growth factors (IGFs). Recent studies have also shown that ligand-induced activation of PRL receptors leads to tyrosine phosphorylation of multiple intracellular proteins, and tyrosine kinase activation takes place in mediating the mitogenic action of PRL. In order to determine whether IGFs are involved in mediating the growth-promoting effect of PRL, rat embryos were culture in vitro for 48 h in whole rat serum and serum depleted of low molecular weight molecules (30 kD retenate) supplemented with rat PRL in the presence and absence of antisera against rat PRL, IGF I and IGF II. To investigate the effects of inhibiting the signal transduction of the PRL receptors, the embryos were preincubated for 2 h in retenate in the presence of tyrosine kinase inhibitors, tyrphostin 47 and genistein, then rat PRL was added to the culture medium. Embryos cultured in retenate showed severe growth retardation, and the addition of rat PRL caused significant increase in growth and development of the embryos suggesting that embryos may be able to utilize maternally derived PRL during organogenesis. The presence of antiserum against rat PRL abolished the PRL-induced increase in development and antibodies against IGF I and II had a similar effect, suggesting that IGFs may be involved in the effect of the hormone. The 2-hour preincubation with genistein and tyrphostin also abolished the PRL-induced increase in development. These results indicate that functional PRL receptors are present in rat embryos at this stage which may play an important role in the control of growth and development and this may be linked to growth factors and their receptors.

1.
Adams, S.O., S.P. Nissley, M. Kasuga, T.P. Foley, M.M. Rechler (1983) Receptors for insulin-like growth factors and growth effects of multiplication-stimulating activity (rat insulin-like growth factor-II) by rat embryo fibroblasts. Endocrinology 112: 971–978.
2.
Akiyama, T., J. Ishida, S. Nakatawa, H. Ogawara, S. Watanabe, N. Itoh, N. Shibuya, Y. Fukami (1987) Genistein, a specific inhibitor of tyrosine-specific protein kinases. J Biol Chem 262: 5592–5595.
3.
Ali, S., I. Pellegrini, P.A. Kelly (1991) A prolactin-dependent immune cell line (Nb2) expresses a mutant form of prolactin receptor. J Biol Chem 266: 20110–20117.
4.
Baker, J., J.P. Liu, E.J. Robertson, A. Efstradiadis (1993) Role of insulin-like growth factors in embryonic and post-natal growth. Cell 75: 73–82.
5.
Baserga, R., R. Rubin (1993) Cell cycle and growth control. Crit Rev Eukaryot Gene Expr 3: 47–61.
6.
Bayatsarmadi, M., L.M. Houdebine (1993) Effect of various protein-kinase inhibitors on the induction of milk protein gene-expression by prolactin. Mol Cell Endocrinol 92: 127–134.
7.
Beck, F., N.J. Samani, J.D. Penshow, B. Thorley, G.W. Tregear, J.P. Coghlan (1987) Histochemical localisation of IGF-I and IGF-II mRNA in the developing rat embryo. Development 101: 175–184.
8.
Buckley, A.R., D.J. Buckley, P.W. Gout, H.Q. Liang, Y.B. Rao, M.J. Blake (1993) Inhibition by genistein of prolactin-induced Nb2 lymphoma cell mitogenesis. Mol Cell Endocrinol 98: 17–25.
9.
Burgaud, J.-L., Baserga (1996) Intracellular transactivation of the insulin-like growth factor I receptor by an epidermal growth factor receptor. Exp Cell Res 223: 412–419.
10.
Butler, S.R., T.W. Hurley, S.M. Schanberg, S. Handwerger (1978) Ovine placental lactogen stimulation of ornithine decarboxylase activity in brain and liver of neonatal rats. Life Sci 22: 2073–2078.
11.
Clements, J., P. Whitfeld, N. Cooke, D. Healy, B. Matheson, J. Shine, J Funder (1983) Expression of the prolactin gene in human decidua-chorion. Endocrinology 112: 1133–1134.
12.
Collins, J.W., S.L. Finley, D. Merrick, E.S. Ogata (1988) Human placental lactogen administration in the pregnant rat; acceleration of fetal growth. Pediatr Res 24: 663–667.
13.
Cowley, E.A., M.K. Pratten (1992) Analysis of the receptor complement for insulin and insulin-like growth factor I (IGF-I) in the rat visceral yolk sac placenta. Biochem Soc Trans 20: 280.
14.
Cowley, E.A., M.K. Pratten (1996) Processing of fluorescently labelled insulin and insulin-like growth factor-I by the rat visceral yolk sac. Placenta 17: 321–327.
15.
Das, R., B.K. Vonderhaar (1996) Activation of RAF-1 MEK, and MAP kinase in prolactin responsive mammary cells. Breast Cancer Res Treat 40: 141–149.
16.
Daughaday, W.H., M. Kapadia (1978) Maintenance of serum somatomedin activity in hypophysectomised pregnant rats. Endorinology 102: 1317–1320.
17.
D’Ercole, A.J., G.T. Applewhite, L.E. Underwood (1980) Evidence that somatomedin is synthesized by multiple tissues in the fetus. Dev Biol 75: 315–328.
18.
D’Ercole, A.J., L.E. Underwood (1981) Growth factors in fetal growth and development; in Novy MJ, JA Resco (eds): Fetal Endocrinology. ORPC Symposia on Reproductive Biology. New York, Academic Press, vol 1, pp 155–182.
19.
Fan, G., P. Carbajo, J.A. Rilemma (1993) Possible role of tyrosine kinases in the prolactin stimulation of cell-division in Nb2 node lymphoma cells. Horm Metab Res 25: 256–258.
20.
Fan, G., J.A. Rilemma (1992) Effect of a tyrosine kinase inhibitor, genistein, on the actions of prolactin in cultured mouse mammary tissues. Mol Cell Endocrinol 83: 51–55.
21.
Ferguson, M.W.J., P.M. Sharpe, B.L. Thomas, F. Beck (1992) Differential expression of insulin-like growth factors I and II (IGF I and II), mRNA, peptide and binding protein 1 during mouse palate development: Comparison with TGF beta peptide distribution. J Anat 181: 219–238.
22.
Florance, R.S.K., P.V. Senior, S. Byrne, F. Beck (1991) The expression of IGF-II in the early post-implantation rat conceptus. J Anat 175: 169–179.
23.
Foley, T.P. Jr., R. DePhilip, A. Perricelli, A. Miller (1980) Low somatomedin activity in cord serum from infants with intrauterine growth retardation. J Pediatr 96: 605–610.
24.
Fowlkes, J., M. Freemark (1993) Placental lactogen-binding sites in isolated fetal fibroblasts: Characterization, processing and regulation. Endocrinology 132: 2477–2483.
25.
Francis, M.J.O., D.J. Hill (1975) Prolactin-stimulated production of somatomedin by rat liver. Nature 255: 167–168.
26.
Freemark, M., A.J. D’Ercole, S. Handwerger (1985) Somatomedin-C stimulates glycogen synthesis in fetal rat hepatocytes. Endocrinology 116: 2578–2582.
27.
Freemark, M., S. Handwerger (1982) Ovine placental lactogen stimulates amino acid transport in rat diaphragm. Endocrinology 110: 2201– 2203.
28.
Freemark, M., S. Handwerger (1984) Ovine placental lactogen stimulates glycogen synthesis in fetal rat hepatocytes. Am J Physiol 246: E21– E24.
29.
Gazit, A., P. Yaish, C. Gilon, A. Levitzki, (1989) Tyrphostins 1. Synthesis and biological activity of protein tyrosine kinase inhibitors. J Med Chem 32: 2344–2352.
30.
Gluckman, P.D., M.W. Brinsmead (1976) Somatomedin in cord blood: Relationship to gestational age and birth size. J Clin Endocrinol Metab 43: 1378–1381.
31.
Grosvenor, C.E. (1967) Disappearance rate of exogenous prolactin from serum of female rats. Endocrinology 80: 195–200.
32.
Gulamhusein, A.P., M.K. Pratten, C.A. Williams, F. Beck (1990) The effect of macromolecular rat serum fractions on conceptuses cultured in human serum: Role of transferrin. J Anat 168: 113–121.
33.
Han, V.K.M., A.J. D’Ercole, P.K. Lund (1987) Cellular localisation of somatomedin (insulin-like growth factor) messenger RNA in the human fetus. Science 236: 193–197.
34.
Han, V.K.M., D.J. Hill (1992) The involvement of insulin-like growth factors in embryonic and fetal development; in Schofield PN (ed): The Insulin-Like Growth Factors. Oxford, Oxford University Press, pp 179–219.
35.
Hill, D.J. (1992) What is the role of growth hormone and related peptides in implantation and the development of the embryo and fetus? J Horm Res 38: 28–34.
36.
Hill, D.J., C.J. Crace, R.D.G. Milner (1985) Incorporation of [3H] thymidine by isolated human fetal myoblasts and fibroblasts in response to human placental lactogen; possible mediation of hPL action by release of somatomedin-C. J Cell Physiol 125: 337–344.
37.
Hill, D.J., B.J.O. Francis, R.D.G. Milner (1977) Action of rat prolactin on plasma somatomedin levels in the rat and on somatomedin release from perfused rat liver. J Endocrinol 75: 137–143.
38.
Hurley, T.W., C.M. Kuhn, S.M. Schanberg, S. Handwerger (1980) Differential effects of placental lactogen, growth hormone and prolactin on rat liver ornithine decarboxylase activity in the perinatal period. Life Sci 27: 2269–2275.
39.
Jacobs, S., P. Cuatrecasas (1986) Phosphorylation of receptors for insulin and insulin-likegrowth factor I: Effects of hormones and phorbol esters. J Biol Chem 263: 934–939.
40.
Karabulut, A.K. (1997) Role of maternally-derived hormonal factors and factors derived from extra-embryonic tissues in mammalian embryos during early organogenesis; PhD thesis, University of Nottingham.
41.
Karabulut, A.K., M.K. Pratten (1995) The growth promoting effects of human placental lactogen and human prolactin in mammalian embryos during early organogenesis. Acta Anat 152: 299.
42.
Karabulut, A.K., M.K. Pratten (1998) Species specificity of growth-promoting effects of prolactin (PRL) during rat embryogenesis. J Anat 192: 1–12.
43.
Kelly, P.A., J. Djiane, M. Katoh, L.H. Ferland, L.E. Houdebine, B. Teyssot, I.D. Fourt (1984) The interaction of prolactin with its receptors in target tissues and its mechanism of action. Recent Prog Horm Res 40: 369–439.
44.
Laemmli, U.K. (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680–685.
45.
Lassare, C., S. Hardouin, F. Daffos, F. Forestier, F. Frankenne, M. Binoux (1991) Serum insulin-like growth factors and insulin-like growth factor binding proteins in the human fetus: Relationship with growth in normal subjects and in subjects with intrauterine growth retardation. Pediatr Res 29: 219–225.
46.
Lebrun, J.J., S. Ali, L. Sofer, A. Ullrich, P.A. Kelly (1994) Prolactin-induced proliferation of Nb2 cells involves tyrosine phosphorylation of the prolactin receptor and its associated tyrosine kinase JAK2. J Biol Chem 269: 14021–14026.
47.
Levitzki, A. (1990) Tyrphostin-potential antiproliferative agents and novel molecular tools. Biochem Pharmacol 40: 913–918.
48.
Levitzki, A. (1992) Tyrphostins: Tyrosine kinase blockers as novel antiproliferative agents and dissectors of signal transduction. FASEB J 6: 3275–3282.
49.
Levitzki, A., C. Gilon (1991) Tyrphostins as molecular tools and potential antiproliferative drugs. Trends Pharmacol Sci 12: 171–174.
50.
Liu, J.P., J. Baker, A.S. Perkins, E.J. Robertson, A. Efstratiadis (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor I (IGF-I) and type 1 IGF receptor (IGF1r). Cell 75: 59–72.
51.
Liu, L., S. Greenberg, S.M. Russell, C.S. Nicoll (1989) Effects of insulin-like growth factors I and II on growth and differentiation of transplanted rat embryos and fetal tissues. Endocrinology 124: 3077–3082.
52.
Lowry, O.H., N.J. Roseborough, A.L. Farr, R.J. Randall (1951) Protein measurement with folin phenol reagent. J Biol Chem 193: 265–275.
53.
Lund, P.K., B.M. Moats-Staats, M.A. Hynes, J.G. Simmons, M. Jansen, A.J. D’Ercole, J. Van Wyk (1986) Somatomedin-C/insulin-like growth factor-I and insulin-like growth factor-II mRNAs in rat fetal and adult tissues. J Biol Chem 261: 14539–14544.
54.
New, D.A.T. (1978) Whole embryo culture and the study of mammalian embryos during organogenesis. Biol Rev 53: 81–122.
55.
Ogren, L., F. Talamantes (1988) Prolactins of pregnancy and their cellular source. Int Rev Cytol 112: 1–65.
56.
Pratten, M.K., A.M. Brooke, S.C. Broome, F. Beck (1988) The effect of epidermal growth factor, insulin and transferrin on the growth promoting properties of serum depleted by repeated culture of postimplantation rat embryos. Development 104: 137–145.
57.
Rao, Y.P., D.J. Buckley, A.R. Buckley (1995a) Rapid activation of mitogen-activated protein kinase and P21 (RAS) by prolactin and interleukin-2 in rat Nb2 lymphoma cells. Cell Growth Differ 6: 1235–1244.
58.
Rao, Y.P., D.J. Buckley, M.D. Olson, A.R. Buckley (1995b) Nuclear translocation of prolactin collaboration of tyrosine kinase and protein-kinase-C activation in rat Nb2 node lymphoma cells. J Physiol 163: 266–276.
59.
Riddick, D.H., W.F. Kusmin (1977) Decidua: A possible source of amniotic fluid prolactin. Am J Obstet Gynecol 127: 187–190.
60.
Riddick, D.H., A.A. Luciano, W.F. Kusmin, I.A. Maslar (1978) De novo synthesis of prolactin by human decidua. Life Sci 23: 1913–1921.
61.
Rilemma, J.A., G.S. Campbell, D.M. Lawson, C. Cartersu (1992) Evidence for a rapid stimulation of tyrosine kinase activity by prolactin in Nb2 rat lymphoma cells. Endocrinology 131: 973–975.
62.
Rotwein, P., K.M. Polock, M. Watson, J.D. Milbrandt (1987) Insulin-like growth factor gene expression during rat embryonic development. Endocrinology 121: 2141–2144.
63.
Rui, H., J.Y. Djeu, G.A. Evans, P.A. Kelly, W.L. Farrar (1992) Prolactin receptor triggering – Evidence for rapid tyrosine kinase activation. J Biol Chem 267: 24076–24081.
64.
Sara, V.R., K. Hall (1980) Somatomedins and the fetus. Clin Obstet Gynecol 23: 765–778.
65.
Sasaki, N., R.W. Rees-Jones, Y. Zick, S.P. Nissley, M.M. Rechler (1985) Characterization of insulin-like growth factor stimulated tyrosine kinase activity associated with β subunit of type I insulin-like growth factor receptors in rat liver cells. J Biol Chem 260: 9793–9804.
66.
Senior, P.V., S. Byrne, W.J. Brammar, F. Beck (1990) Expression of the IGF-II/mannose-6-phosphate receptor mRNA and protein in the developing rat. Development 109: 67–73.
67.
Sharpe, P.M., C.L. Brunet, M.W.J. Ferguson (1992) Modulation of the epidermal growth factor of mouse embryonic mesenchymal cells in vitro by growth factors. Int J Dev Biol 36: 275–282.
68.
Shastry, B.S. (1994) More to learn from gene knockouts. Mol Cell Biochem 136: 171–182.
69.
Smith, E.P., T.W. Sadler, A.J. D’Ercole (1987) Somatomedins/insulin-like growth factors, their receptors and binding proteins are prsent during mouse embryogenesis. Development 101: 73–82.
70.
Tebbs, C.A. (1997) Maternally derived growth regulating factors for mammalian embryos during early organogenesis; PhD thesis, University of Nottingham.
71.
Tebbs, C.A., P.F.T. Cumberland, M.K. Pratten (1997) The role of maternally derived epidermal growth factor receptor during organogenesis in the rat embryo. J Anat 190: 491–503.
72.
Van Maele-Fabry, G., F. Delhaise, J.J. Picard (1990) Morphogenesis and quantification of the development of post-implantation mouse embryos. Toxicol In Vitro 4: 149–156.
73.
Wilcox, J.N., R. Derynck (1988) Developmental expression of transforming growth factors alpha and beta in mouse fetus. Mol Cell Biol 8: 3415–3422.
74.
Williams, C.L., P.K. Priscott, I.T. Oliver, G.C. Yeoh (1986) Albumin and transferrin synthesis in whole rat embryo cultures. J Embryol Exp Morphol 92: 33–41.
75.
Wu, Y.L., M. Tewari, S. Cui, R. Rubin (1996) Activation of the insulin-like growth factor receptor inhibits tumor necrosis factor induced cell death. J Cell Physiol 168: 499–509.
76.
Yu, K.T., M.A. Peters, M.P. Czech (1986) Similar control mechanisms regulate the insulin and type I insulin-like growth factor tyrosine kinases. J Biol Chem 261: 11341–11349.
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