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Endocrinology Vol. 141, No. 7 2691-2697
Copyright © 2000 by The Endocrine Society

ARTICLES

Rescue of Preimplantatory Egg Development and Embryo Implantation in Prolactin Receptor-Deficient Mice after Progesterone Administration

Nadine Binart, Christine Helloco, Christopher J. Ormandy, Jacqueline Barra, Philippe Clément-Lacroix, Nathalie Baran and Paul A. Kelly

INSERM, U-344, Endocrinologie Moléculaire, Faculté de Médecine Necker (N.B., C.H., P.C.-L., N.B.), 75730 Paris, France; Cancer Research Program, Garvan Institute of Medical Research (C.J.O.), Darlinghurst, New South Wales 2010, Sydney, Australia; and Unité de Biologie du Développement, Institut Pasteur (J.B.), Paris 75015, France

Address all correspondence and requests for reprints to: Dr. Nadine Binart, INSERM, U-344, Endocrinologie Moléculaire, Faculté de Médecine Necker, 156 rue de Vaugirard, 75730 Paris Cedex 15, France. E-mail: binart{at}necker.fr


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PRL, a hormone secreted essentially by the pituitary and other extrapituitary sources such as decidua, has been attributed regulatory roles in reproduction and cell growth in mammals. These effects are mediated by a membrane PRL receptor belonging to the cytokine receptor superfamily. Null mutation of the PRL receptor gene leads to female sterility due to a severely compromised preimplantation development and a complete failure of the implantation of the few embryos reaching the blastocyst stage, strongly implicating PRL in the maternal control of implantation. We measured the hormonal status of -/- mice, which confirmed that the corpus luteum is unable to produce progesterone. Progesterone administration to -/- mice completely rescued the development of preimplantatory eggs and embryo implantation. Pregnancy could be maintained to 19.5 days postcoitum, with about 22% of resulting embryos reaching adulthood. Although progesterone and perhaps PRL appear to facilitate mouse preembryo development throughout the preimplantation stages, other factors as well as a possible direct effect of PRL on the uterus are probably necessary to fully maintain pregnancy. Finally, reduced ductal side-branching in the mammary gland can be rescued by progesterone treatment, but females exhibit reduced alveolar formation. Our model establishes the PRL receptor as a key regulator of reproduction and provides novel insights into the function of lactogenic hormones and their receptor.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PRL IS a pleiotropic pituitary hormone (300 distinct reported biological functions), long known for its luteotropic actions in the rodent (1, 2, 3, 4). Recently, PRL has been shown to regulate multiple genes and events in ovarian follicular development and function, as evidenced by our recently reported PRL receptor (PRLR) null mutant mice (5). Moreover, we identified altered maternal behavior in these animals (6) and an effect of PRL on osteoblasts affecting normal bone formation and maintenance of bone mass (7). Female -/- mice never become pregnant and fail to establish pseudopregnancy, indicating impaired function of the corpus luteum (CL). Null mice also had fewer follicles, reduced ovulation, delayed or mistimed oocyte release, and impaired oocyte maturation, all signs of disruption in follicular development before luteinization. The basis of the sterility of PRLR mutant mice is attributed to multiple causes, in particular to the absence of sufficient progesterone to support implantation and subsequent placental development and maintenance. The importance of progesterone in ovarian and uterine functions is evident from the phenotype of progesterone receptor-deficient mice (8). The primary site of production of progesterone during pregnancy in the mouse is the CL of the ovary. PRL participates in regulating the CL in the pregnant rodent ovary (9, 10). The lack of CL development would therefore be expected to have a significant effect on circulating levels of progesterone.

Multiple murine PRL receptors are encoded by alternatively spliced messenger RNAs (mRNAs), and the expression of the mRNAs encoding the four distinct forms of the PRL receptor was reported in the mature mouse ovary during pregnancy (11). Cell-cell interactions between the blastocyst trophectoderm and uterine luminal epithelium are essential to the process of implantation. The factors that participate in these interactions or their mechanisms of action are poorly understood. Although the absolute requirement for progesterone for the maintenance of pregnancy in mammals is well known, there have been few studies that establish to what extent the level of progesterone support required may change as pregnancy progresses. In mice, ovariectomy at any stage of pregnancy results in resorption of the fetuses or abortion (12). Activation of the PRL receptor by binding of one of these ligands (PRL, placenta lactogen I, and placenta lactogen II) leads to a variety of molecular, cellular, and physiological responses, including the induced transcription and stabilization of several mRNAs, the stimulation of cell proliferation or differentiation, and the development and maintenance of structures such as the CL in the ovary and the ducts and alveoli in the mammary gland (13). When female PRLR-/- mice were bred, they were found to be infertile. Mating of these females with fertile males of any genotype, aged 6–12 months, never resulted in clinically detectable pregnancy or the production of offspring. We report here that the defect of preimplantation egg development in these mice is completely rescued by the addition of progesterone. Although implantation occurs, the maintenance of full-term pregnancy is not complete.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
Knockout mice were generated as previously described (5). Mice were kept, two per cage, at 25 C with a 12-h light, 12-h dark cycle; they were fed a pelleted diet ad libitum. Heterozygous mutants (129SvJ) were bred to produce -/-, +/-, and +/+ animals. Pups were genotyped by PCR amplification using the following primers: wild-type forward, 5'-GAGAAAAACACCTATGAATGT-3'; Neo forward, 5'-CCAGTCCCTTCCCGCTTCAGT-3'; and common reverse, 5'-GAAGAGCAAGATCTCAAGAAC-3'. Day 0.5 of pregnancy was taken as the day the vaginal plug was found; females were isolated from males on this day. Progesterone with biodegradable carrier binder (Innovative Research of America, Toledo, OH) was administered in 5-mg pellets for a 3-week release. All experimental designs and procedures are in agreement with the guidelines of the animal ethics committee of the Ministère de l’Agriculture.

Hormone measurements
Mice were anesthetized, and blood was collected by cardiac puncture. Blood was centrifuged, and serum was assayed for PRL, estradiol, and progesterone by RIA. The serum concentration of PRL was established using an immunoassay with a polyclonal rabbit antibody directed specifically against mouse PRL (a gift from Dr. F. Talamantes). Estradiol and progesterone were measured in individual serum samples from 3-month-old animals using human RIA kits (Immunotech, Paris, France; reference no. 1663 and 1188, respectively). The levels of steroid hormones were measured on days 0.5, 1.5, 2.5, and 3.5 after observation of the vaginal plug. The values are the mean ± SEM (n = 8–12 for each group).

Recovery and staging of preimplantation embryos
Embryos were recovered from the oviduct as previously described. Oviducts were flushed with Whitten’s medium (14) to recover eggs or embryos, and their morphologies were examined under a microscope. They were classed as follows: one- and two-cell embryos, morula, and blastocyst.

Recovery of embryos
Embryos were recovered from both uterine horns. The number of implantation sites was recorded. Live embryos as well as resorption sites were counted at the indicated times after observation of the vaginal plug.

Histology of mammary glands
The fourth inguinal mammary glands from PRLR+/+ and PRLR-/- mice were removed and fixed in 4% formalin. Whole mounts were performed as previously described (15), using carmin alum staining. Formalin-fixed specimens were paraffin embedded and serially sectioned (5 µm) before hematoxylin-eosin-safran staining.

Statistics
The significance of differences between groups was evaluated with ANOVA and Student’s t test.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Hormonal status of -/- mice
The concentration of circulating PRL was evaluated by RIA in virgin +/+, +/-, and -/- females (Fig. 1Go). Levels of circulating PRL were dramatically increased (30- to 100-fold) in -/- females due to the absence of the receptor, whereas heterozygous mice were indistinguishable from their wild-type littermates with respect to PRL concentration.



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  		Figure 1. Serum PRL concentrations in +/+, +/-, and -/- virgin female mice. Bars represent the mean ± SEM (n = 8–12). The asterisk indicates a statistically significant difference between wild-type (+/+) and PRLR-deficient (-/-) mice (P < 0.05, evaluated by ANOVA and Duncan’s test).

 
Serum was assayed for hormone levels only from mice that showed evidence of successful mating. We measured serum estradiol and progesterone levels in adult females 0.5, 1.5, 2.5, and 3.5 days after ovulation; these values are presented in Fig. 2Go, A and B, respectively. Homozygous mutants exhibited a slight decrease in estradiol levels. Progesterone levels were diminished from day 1.5, confirming the importance of PRL, even at this early stage, in the maintenance of progesterone secretion.



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  		Figure 2. Open and closed symbols represent steroid levels in wild-type and PRLR-/- mice, respectively. A. Serum estradiol levels; B, serum progesterone levels. Values are expressed as the mean ± SEM.

 
Preimplantatory development of eggs
The preimplantation development of embryos in PRLR+/+ and PRLR-/- females after mating to PRLR+/+ or PRLR-/- fertile males was analyzed, because multiple abnormalities were previously observed in the -/- females (5). Single cell fertilized eggs were recovered at all stages studied, suggesting that for most oocytes a developmental arrest occurred immediately after fertilization. Fertilized eggs developed poorly, with only 19% of blastocysts recovered at day 3.5. Preimplantation development of embryos in PRLR-/- females was studied after administration of a progesterone pellet 12 h (day 0.5) after ovulation, i.e. at the time the vaginal plug was observed. Embryos were flushed from the oviduct at various times, and their stage of development was determined (see Table 1Go). Expression of results was performed by the percentage of recovered eggs at each analyzed stage, as the number of eggs ovulated was reduced in PRLR-/- mice.


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  		Table 1. Preimplantation development of eggs from PRLR+/+, PRLR-/-, and progesterone (P4)-treated PRLR-/- mice from days 0.5–3.5

 
On day 2.5, 70% of morula were recovered in the uteri of progesterone-treated PRLR-/- females vs. 7% in untreated animals. Blastocysts recovered on day 3.5 represented 74% of the total population, a value not statistically different from that observed in wild-type females (87%). Thus, under these experimental conditions, a complete rescue of egg development was seen by progesterone treatment of PRLR-/- females.

Maintenance of pregnancy until delivery
As the presence of a near-normal number of blastocysts was seen on day 3.5 in the uterus of progesterone-treated PRLR-/- females, we decided to permit pregnancy to continue to the time of normal parturition to examine whether the uterus was able to accept embryo implantation. The results are presented in Fig. 3Go. Knowing that the window of implantation occurs between days 3.5–4, we began to verify the presence of normal embryos and resorption sites from day 8.5. Subcutaneous delivery of progesterone clearly had a beneficial effect on the maintenance of embryos during the first half of pregnancy. However, an increasing number of resorption sites was seen between days 12.5–19.5. Despite the fact that a large number of embryos was lost from midgestation, 22% of the embryos remained viable. On day 19.5, we performed cesarean sections, and a total of 12 live pups were observed to have developed normally. In wild-type females on the 129 Sv background the average number of ovulated eggs is 11.4, but the average litter size is only 9.4; in young females (3–5 months), up to 30% of the embryos are routinely resorbed in utero during pregnancy. To ascertain that progesterone delivery via the implants was effective, we measured circulating levels of progesterone. Values were on the same order of magnitude as in pregnant wild-type animals. For example, the serum progesterone level was 237 ng/ml (+/+) on day 17.5 vs. 191 ng/ml (-/-; rescued) and 120 ng/ml (+/+) on day 18.5 vs. 166 ng/ml (-/-; rescued).



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  		Figure 3. Rescue of implantation between 8.5 and 19.5 days post coïtum. The number of embryos (white bars) and resorption sites (hatched bars) are represented as the mean ± SEM at the indicated times of five individual experiments at all stages of pregnancy except for days 15.5 and 19.5, when 10 and 12 independent experiments were performed, respectively.

 
Histology of mammary gland development
At the onset of puberty, the mammary rudiments of ductal architecture transform, and ductal elongation and bifurcations begin. Previous data indicated that the glands showed reduced ductal side-branching in PRLR-/- females, whereas the terminal end buds of the major mammary ducts and side-branches in wild-type animals had differentiated to yield alveolar buds (16). During pregnancy, alveolar buds previously formed on the ductal tree gave rise to lobulo-alveolar structures capable of milk production. The mammary glands from virgin -/- females were compared with those from progesterone-treated animals on day 18.5 of pregnancy. By whole mount analysis, ductal branching was able to develop, as indicated in Fig. 4Go. The increase in ductal branching was extensive after administration of progesterone; however, treatment with progesterone and estradiol did not improve alveolar development. Histological analysis of the PRLR-/- females able to maintain pregnancy until day 18.5 was compared with that of wild-type animals at the same stage (Fig. 5Go). The formation of alveolar bud was present, but lobulo-alveolar development was very reduced despite the absence of PRLR.



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  		Figure 4. Ductal branching development of virgin wild-type, virgin knockout, and pregnant knockout mice. The fourth inguinal mammary gland was analyzed using whole mount histology in a virgin wild-type mouse (a), a virgin -/- mouse (b), and on day 18.5 of pregnancy in a -/- mouse (c). All females were 12 weeks old. Magnification, x5.

 


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  		Figure 5. Histological analysis of mammary glands from pregnant +/+ and -/- progesterone-treated females on day 18.5. Hematoxylin/eosin-stained sections through the skin, sc fat, mammary fad pad, and epithelium are shown. PRLR+/+ female (a, c, and e) and PRLR-/- female (b, d, and f) mice treated with progesterone at the same stage of pregnancy are shown. Magnification, x40 (a and b), x100 (c and d), and x250 (e and f).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We analyzed reproductive and hormonal characteristics of PRLR knockout mice and found endocrine abnormalities associated with the absence of PRLR expression in these animals. PRLR-/- mice exhibited an alteration of estrous cyclicity, as evidenced by vaginal cytology, and a marked reduction in progesterone secretion. A decreased level of circulating estradiol was also seen. These results implicate the PRLR as a key component regulating ovarian function governing the normal regulation of progesterone secretion.

Our results are the first to demonstrate that PRL probably has a direct effect on the regulation of its own secretion at the hypothalamic or pituitary level, or both. In the anterior pituitary, spontaneous PRL release from lactotrophs is tonically inhibited by activation of D2 receptors (17). Mice with a disrupted D2 dopamine receptor gene had chronic hyperprolactinemia (although much less than that seen with PRL-/- mice) and developed anterior lobe lactotroph hyperplasia (18). A decrease in dopamine is probably involved in our mouse model, because the administration of D2 dopamine receptor agonists such as bromocriptine was able to drastically reduce PRL levels to near normal (data not shown). Most anterior pituitary hormones are regulated via negative feedback exerted by circulating hormones, but there is no known peripheral regulator for PRL. Thus, the feedback mechanism must be either direct, on dopamine secretory neurons, or indirect, via some as yet undiscovered factor.

The mechanism by which the LH surge induces granulosa cells to undergo rapid reprogramming and terminal differentiation to become luteal cells is not well understood, but involves the acquisition of PRL responsiveness, a process requisite for maintenance of luteal cell function. Previous studies have detailed the temporal requirements for the CL to maintain and produce progesterone by pituitary PRL and LH during rat pregnancy (19). Measurements of progesterone concentration during early pregnancy in the mouse showed that there was a significant rise in plasma levels before implantation (20). The results of this investigation in the wild-type females are in good agreement with reported values. However in the -/- mice, progesterone levels were very low. Thus, the result of lack of trophic support of the CL by PRL is a reduction of progesterone levels in early pregnancy. The failure of preimplantation egg development in PRLR-/- females is clear at the first stages of pregnancy. These results indicate that PRL must trigger an early signal to the CL. The targeted disruption of the progesterone receptor gene resulted in a complete block of ovulation in mice, and morphological analysis of ovaries revealed a conspicuous absence of CL and the presence of an unexpectedly large number of mature preovulatory type follicles (8). This model provides strong in vivo evidence for an important functional role for progesterone receptor in the luteinization process. In our model, the low level of progesterone remaining appears to be enough to induce ovulation, but not to ensure normal preimplantation development. The rescue of egg development before implantation is almost complete after administration of an adapted support of exogenous progesterone, highlighting the importance of this steroid synthesis. The rescue of preimplantation egg development reaches 74% vs. 87% of the total eggs observed in wild-type animals on day 3.5, suggesting that progesterone could act via factors from tubal epithelial cells that may facilitate the development of mouse eggs throughout the preimplantation stages. High levels of PRL secreted by the pituitary are not functional due to the lack of the receptor; consequently, appropriate progesterone and estrogen signals are not present for implantation. Although there have been a number of isolated studies of the endocrine requirements for maintenance of pregnancy after ovariectomy in both mice and rats, these have largely been conducted over very limited stages of pregnancy and using steroid injections as the basis of the replacement regimen. Low concentrations of progesterone in the luteal phase have been reported to be associated with reduced embryo survival (21). The establishment and maintenance of pregnancy required different minimum progesterone levels (22). Our experimental conditions are in good agreement with the circulating concentrations that have been reported.

At midpregnancy, a further change in the minimum endocrine requirements appears to coincide with the time at which both progesterone (23) and estradiol (24) concentrations normally increase. Under our experimental conditions where progesterone is delivered at a constant rate, we still observed an increasing number of resorption sites starting on day 12.5. Previous studies have shown the essential role of estrogen in maintenance of the CL and production of progesterone during rat pregnancy (25). Daily addition of 1 µg estradiol to the mice at midpregnancy was not able to improve these results (two embryos and two resorption sites recovered on day 18.5 in five independent experiments). We thus conclude that these defects are not only the result of a deficiency of ovarian steroid hormones, but also that PRL could play a direct or indirect role (via some unknown factors) on the maintenance of pregnancy. Moreover, the synthesis of PRL in decidua has been reported, and PRLR gene expression has previously been observed in many different tissues (26). The PRL gene and its receptor are expressed in the uterus (27), suggesting that this might also have some potential for a paracrine or autocrine effect. Overall, these observations indicate that preventing PRL action by disruption of the PRLR gene alters the maternal decidual transformation in response to the implanting blastocyst, demonstrating an essential role of PRL in reproduction. PRLR expression has also been reported in human endometrial tissue (27). The spatio-temporal expression of the receptor gene has been now studied (27A ). PRL is known to be expressed in the decidualized human endometrium and secreted into amniotic fluid. By using in situ hybridization histochemistry techniques, PRL-specific hybridization signals were distributed over the decidual cells in early and term pregnancy. It would be interesting to determine whether the production of PRL or the expression of PRLR is altered in pathological conditions associated with female sterility.

Like other PRL-responsive tissues, Stat5 proteins are essential for the development of functional CL in the ovary (28). This is consistent with the critical role that PRL has in ovarian function based on the female infertility of both PRL-deficient (29) and PRLR-deficient (5) mice. When placentation occurs, the high level of circulating PRL might give rise to 16K fragments, which could exert an antiangiogenic property on the uterus (30). PRL (and placental lactogens), which stimulate cell proliferation, could have an opposing action, and thus the balance between PRL and 16K PRL might be important in the regulation of tissue growth in the context of angiogenesis and maintenance of placenta vascularization (31). The high abortion rate from day 12.5 could be a result of this effect. The analysis of the mammary phenotype in PRLR-deficient mice was previously complicated by the fact that the reproductive function affecting mammary gland development was altered in the female. Systemic endocrine effects or the inability of the mammary epithelium to respond to PRL should be responsible for the persistence of endbud-like structures at the ductal ends and of poor ductal branching. Similar defects in ductal branching and end bud differentiation are seen in mice lacking PRL (29) or the transcription factor Stat5a (32). Progesterone is required for ductal branching (33), and the addition of this steroid to maintain the pregnancy is also able to rescue ductal side-branching in PRLR-/- females, as ductal bifurcation appeared to be normal. However, the treatment by progesterone and estradiol does not improve alveolar development. Lobulo-alveolar development during pregnancy is under the control of both PRL and progesterone; in the pregnant -/- females it is reduced, but not completely absent, indicating that some other growth factor or cytokine signaling pathways can partially compensate for the effect of PRL.

The last decade has seen the identification of polypeptide growth factors and cytokines as mediators of many of the growth-promoting properties of steroid hormones as well as components of materno-embryo signaling at the implantation site. Cytokines have long been thought to play important roles in the events surrounding implantation (34). Rodent models have produced a plethora of data from which a number of molecules have been strongly implicated in regulating uterine remodeling, implantation, and the placenta. The collective and coordinate action of these molecules on uterine and extra-embryonic cells is likely to be a major mechanism by which pregnancy is successfully established and maintained (35).

To more fully understand the molecular mechanisms involved in PRL-mediated events in the oviduct and uterus, we are using PRLR-deficient mice and differential display technology to identify and characterize new gene targets of PRL. In-depth molecular characterization should help to elucidate the actual control mechanisms as well as PRL-dependent signaling pathways that are involved in the early stages of pregnancy.


   Acknowledgments
 
We thank Dr. Frank Talamantes for his kind gift of PRL antibody, Gérard Pivert for the preparation of histological sections, and Drs. Philippe Touraine and Vincent Goffin for helpful discussions, support, and critical reading of the manuscript. We also thank very kindly Claudine Coridun for secretarial assistance.

Received December 23, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Gibori G 1992 The corpus luteum of pregnancy. In: Adashi EY, Leung PCK (eds) The Ovary. Raven Press, New York, pp 261–317
  2. Armstrong DT, Knudsen KA, Miller LS 1970 Effects of prolactin upon cholesterol metabolism and progesterone biosynthesis in corpora lutea of rats hypophysectomized during pseudopregnancy. Endocrinology 86:634–641[Abstract/Free Full Text]
  3. Ota H, Wakizaka A, Fukushima M, Maki M 1985 Dual regulation of rat ovarian LH-receptor by the administration of prolactin or sulpiride. IRCS Med Sci 63:257–264
  4. Berhman HR, Orczyk GP, MacDonald GJ, Greep RO 1970 Prolactin induction of enzymes controlling luteal cholesterol ester turnover. Endocrinology 87:1251–1256[Abstract/Free Full Text]
  5. Ormandy CJ, Camus A, Barra J, Damotte D, Lucas BK, Buteau H, Edery M, Brousse N, Babinet C, Binart N, Kelly PA 1997 Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. Genes Dev 11:167–178[Abstract/Free Full Text]
  6. Lucas BK, Ormandy C, Binart N, Bridges RS, Kelly PA 1998 Null mutation of prolactin receptor gene produces a defect in maternal behavior. Endocrinology 139:4102–4107[Abstract/Free Full Text]
  7. Clement-Lacroix P, Ormandy C, Lepescheux L, Ammann P, Damotte D, Goffin V, Bouchard B, Amling M, Gaillard-Kelly M, Binart N, Baron R, Kelly PA 1999 Osteoblasts are a new target for prolactin: analysis of bone formation in prolactin receptor knockout mice. Endocrinology 140:96–105[Abstract/Free Full Text]
  8. Lydon JP, DeMayo FJ, Funk CR, Mani SK, Hughes CA, Montgomery CA, Shyamala G, Conneely OM, O’Malley BW 1995 Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes Dev 9:2266–2278[Abstract/Free Full Text]
  9. Smith MS 1980 Role of prolactin in mammalian reproduction. Int Rev Physiol 22:249–276[Medline]
  10. Rothchild I 1981 The regulation of the mammalian corpus luteum. Recent Prog Horm Res 37:183–298
  11. Clarke DL, Linzer DH 1993 Changes in prolactin receptor expression during pregnancy in the mouse ovary. Endocrinology 133:224–232[Abstract/Free Full Text]
  12. Rubinstein P, Forbes TR 1963 Maintenance of pregnancy with subcutaneous pellets of progesterone in ovariectomized mice. Proc Soc Exp Biol Med 113:1043–1046
  13. Vonderhaar BK 1988 Regulation of development of the normal mammary gland by hormones and growth factors. Cancer Treat Res 40:251–266[Medline]
  14. Whitten WK, Biggers JD 1968 Complete development in vitro of the pre-implantation stages of the mouse in a simple chemically defined medium. J Reprod Fertil 17:399–401[Abstract/Free Full Text]
  15. Medina D 1973 Preneoplastic lesions in mouse mammary tumorigenesis. In: Methods in Cancer Research. Academic Press, New York, pp 3–53
  16. Brisken C, Kaur S, Chavarria TE, Binart N, Sutherland RL, Weinberg RA, Kelly PA, Ormandy CJ 1999 Prolactin controls mammary gland development via direct and indirect mechanisms. Dev Biol 210:96–106[CrossRef][Medline]
  17. Ben-Jonathan N, Mershon JL, Allen DL, Steinmetz RW 1996 Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects. Endocr Rev 17:639–669[Abstract/Free Full Text]
  18. Kelly MA, Rubinstein M, Asa SL, Zhang G, Saez C, Bunzow JR, Allen RG, Hnasko R, Ben-Jonathan N, Grandy DK, Low MJ 1997 Pituitary lactotroph hyperplasia and chronic hyperprolactinemia in dopamine D2 receptor-deficient mice. Neuron 19:103–113[CrossRef][Medline]
  19. Morishige WK, Rothchild I 1974 Temporal aspects of the regulation of corpus luteum function by luteinizing hormone, prolactin and placental luteotrophin during the first half of pregnancy in the rat. Endocrinology 95:260–274[Abstract/Free Full Text]
  20. Gidley-Baird AA 1977 Plasma progesterone, FSH and LH levels associated with implantation in the mouse. Aust J Biol Sci 30:289–296[Medline]
  21. Wilmut I, Sales DI, Ashworth CJ 1986 Maternal and embryonic factors associated with prenatal loss in mammals. J Reprod Fertil 76:851–864[Abstract/Free Full Text]
  22. Milligan SR, Finn CA 1997 Minimal progesterone support required for the maintenance of pregnancy in mice. Hum Reprod 12:602–607
  23. Murr SM, Stabenfeldt GH, Bradford GE, Geschwind II 1974 Plasma progesterone during pregnancy in the mouse. Endocrinology 94:1209–1211[Abstract/Free Full Text]
  24. Barkley MS, Michael SD, Geschwind II, Bradford GE 1977 Plasma testosterone during pregnancy in the mouse. Endocrinology 100:1472–1475[Abstract/Free Full Text]
  25. Gibori G, Rodway R, Rothchild I 1977 The luteotrophic effect of estrogen in the rat: prevention by estradiol of the luteolytic effect of an antiserum to luteinizing hormone in the pregnant rat. Endocrinology 101:1683–1689[Abstract/Free Full Text]
  26. Freemark M, Driscoll P, Andrews J, Kelly PA, Royster M 1996 Ontogenesis of prolactin receptor gene expression in the rat olfactory system: potential roles for lactogenic hormones in olfactory development. Endocrinology 137:934–942[Abstract]
  27. Tanaka S, Koibuchi N, Ohtake H, Ohkawa H, Kawatsu T, Tadokoro N, Kumasaka T, Inaba N, Yamaoka S 1996 Regional comparison of prolactin gene expression in the human decidualized endometrium in early and term pregnancy. Eur J Endocrinol 135:177–183[Abstract/Free Full Text]
  28. Reese J, Binart N, Brown N, Ma WG, Paria BC, Das SK, Kelly PA, Dey SK 2000 Implantation and decidualization defects in prolactin receptor (PRLR)-deficient mice are mediated by ovarian but not uterine PRLR [In Process Citation]. Endocrinology 141:1872–1881
  29. Teglund S, McKay C, Schuetz E, Van Deursen JM, Stravopodis D, Wang D, Brown M, Bodner S, Grosveld G, Ihle JN 1998 Stat5a and Stat5b proteins have essential and nonessential, or redundant, roles in cytokine responses. Cell 93:841–850[CrossRef][Medline]
  30. Horseman ND, Zhao W, Montecino-Rodriguez E, Tanaka M, Nakashima K, Engle SJ, Smith F, Markoff E, Dorshkind K 1997 Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene. EMBO J 16:6926–6935[CrossRef][Medline]
  31. Clapp C, Martial JA, Guzman RC, Rentier-Delrue F, Weiner RI 1993 The 16-kilodalton N-terminal fragment of human prolactin is a potent inhibitor of angiogenesis. Endocrinology 133:1292–1299[Abstract/Free Full Text]
  32. Bentzien F, Vigne JL, Weiner RI, Taylor RN Potential role of cathepsin D in the formation of antiangiogenic fragments of prolactin in the human endometrium. 79th Annual Meeting of The Endocrine Society, Las Vegas, NV, 1997, p 143 (Abstract)
  33. Liu X, Robinson GW, Wagner KU, Garrett L, Wynshaw-Boris A, Hennighausen L 1997 Stat5a is mandatory for adult mammary gland development and lactogenesis. Genes Dev 11:179–186[Abstract/Free Full Text]
  34. Brisken C, Park S, Vass T, Lydon JP, O’Malley BW, Weinberg RA 1998 A paracrine role for the epithelial progesterone receptor in mammary gland development. Proc Natl Acad Sci USA 95:5076–5081[Abstract/Free Full Text]
  35. Chard T 1995 Cytokines in implantation. Hum Reprod Update 1:385–396[Abstract/Free Full Text]
  36. Surveyor GA, Wilson AK, Brigstock DR 1998 Localization of connective tissue growth factor during the period of embryo implantation in the mouse. Biol Reprod 59:1207–1213[Abstract/Free Full Text]



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J. Halperin, S. Y. Devi, S. Elizur, C. Stocco, A. Shehu, D. Rebourcet, T. G. Unterman, N. D. Leslie, J. Le, N. Binart, et al.
Prolactin Signaling through the Short Form of Its Receptor Represses Forkhead Transcription Factor FOXO3 and Its Target Gene Galt Causing a Severe Ovarian Defect
Mol. Endocrinol., February 1, 2008; 22(2): 513 - 522.
[Abstract] [Full Text] [PDF]

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 Poult. Sci.Home page
Z. Kang, G. Y. Bedecarrats, and D. Zadworny
Expression Patterns of the Prolactin Receptor Gene in Chicken Lymphoid Tissues During Embryogenesis and Posthatch Period
Poult. Sci., November 1, 2007; 86(11): 2404 - 2412.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
L. Bao, C. Tessier, A. Prigent-Tessier, F. Li, O. L. Buzzio, E. A. Callegari, N. D. Horseman, and G. Gibori
Decidual Prolactin Silences the Expression of Genes Detrimental to Pregnancy
Endocrinology, May 1, 2007; 148(5): 2326 - 2334.
[Abstract] [Full Text] [PDF]

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 ReproductionHome page
A. Bachelot and N. Binart
Reproductive role of prolactin
Reproduction, February 1, 2007; 133(2): 361 - 369.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
D. Piwnica, I. Fernandez, N. Binart, P. Touraine, P. A. Kelly, and V. Goffin
A New Mechanism for Prolactin Processing into 16K PRL by Secreted Cathepsin D
Mol. Endocrinol., December 1, 2006; 20(12): 3263 - 3278.
[Abstract] [Full Text] [PDF]

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 Hum Reprod UpdateHome page
K.R. Barnett, C. Schilling, C.R. Greenfeld, D. Tomic, and J.A. Flaws
Ovarian follicle development and transgenic mouse models
Hum. Reprod. Update, September 1, 2006; 12(5): 537 - 555.
[Abstract] [Full Text] [PDF]

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 Mol. Endocrinol.Home page
J. Harris, P. M. Stanford, K. Sutherland, S. R. Oakes, M. J. Naylor, F. G. Robertson, K. D. Blazek, M. Kazlauskas, H. N. Hilton, S. Wittlin, et al.
Socs2 and Elf5 Mediate Prolactin-Induced Mammary Gland Development
Mol. Endocrinol., May 1, 2006; 20(5): 1177 - 1187.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
Z. Cai and C. Stocco
Expression and Regulation of Progestin Membrane Receptors in the Rat Corpus Luteum
Endocrinology, December 1, 2005; 146(12): 5522 - 5532.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
C. Kedzia, L. Lacroix, N. Ameur, T. Ragot, P. A. Kelly, B. Caillou, and N. Binart
Medullary Thyroid Carcinoma Arises in the Absence of Prolactin Signaling
Cancer Res., September 15, 2005; 65(18): 8497 - 8503.
[Abstract] [Full Text] [PDF]

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 J Mol EndocrinolHome page
S Viengchareun, H Bouzinba-Segard, J-P Laigneau, M-C Zennaro, P A Kelly, A Bado, M Lombes, and N Binart
Prolactin potentiates insulin-stimulated leptin expression and release from differentiated brown adipocytes
J. Mol. Endocrinol., December 1, 2004; 33(3): 679 - 691.
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 DevelopmentHome page
W. Long, K.-U. Wagner, K. C. K. Lloyd, N. Binart, J. M. Shillingford, L. Hennighausen, and F. E. Jones
Impaired differentiation and lactational failure of Erbb4-deficient mammary glands identify ERBB4 as an obligate mediator of STAT5
Development, November 1, 2003; 130(21): 5257 - 5268.
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 EndocrinologyHome page
N. Binart, N. Melaine, C. Pineau, H. Kercret, A. M. Touzalin, P. Imbert-Bollore, P. A. Kelly, and B. Jegou
Male Reproductive Function Is Not Affected in Prolactin Receptor-Deficient Mice
Endocrinology, September 1, 2003; 144(9): 3779 - 3782.
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 EndocrinologyHome page
C. Stocco, J. Djiane, and G. Gibori
Prostaglandin F2{alpha} (PGF2{alpha}) and Prolactin Signaling: PGF2{alpha}-Mediated Inhibition of Prolactin Receptor Expression in the Corpus Luteum
Endocrinology, August 1, 2003; 144(8): 3301 - 3305.
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 EndocrinologyHome page
E. Saunier, F. Dif, P. A. Kelly, and M. Edery
Targeted Expression of the Dominant-Negative Prolactin Receptor in the Mammary Gland of Transgenic Mice Results in Impaired Lactation
Endocrinology, June 1, 2003; 144(6): 2669 - 2675.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
C. Tessier, A. Prigent-Tessier, L. Bao, C. M. Telleria, S. Ferguson-Gottschall, G. B. Gibori, Y. Gu, J. M. Bowen-Shauver, N. D. Horseman, and G. Gibori
Decidual Activin: Its Role In the Apoptotic Process and Its Regulation by Prolactin
Biol Reprod, May 1, 2003; 68(5): 1687 - 1694.
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 Biol. Reprod.Home page
N. Baran, P. A. Kelly, and N. Binart
Decysin, a New Member of the Metalloproteinase Family, Is Regulated by Prolactin and Steroids During Mouse Pregnancy
Biol Reprod, May 1, 2003; 68(5): 1787 - 1792.
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 Recent Prog Horm ResHome page
C. J. Ormandy, M. Naylor, J. Harris, F. Robertson, N. D. Horseman, G. J. Lindeman, J. Visvader, and P. A. Kelly
Investigation of the Transcriptional Changes Underlying Functional Defects in the Mammary Glands of Prolactin Receptor Knockout Mice
Recent Prog. Horm. Res., January 1, 2003; 58(1): 297 - 323.
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 Mol. Endocrinol.Home page
S. L. Grimm, T. N. Seagroves, E. B. Kabotyanski, R. C. Hovey, B. K. Vonderhaar, J. P. Lydon, K. Miyoshi, L. Hennighausen, C. J. Ormandy, A. V. Lee, et al.
Disruption of Steroid and Prolactin Receptor Patterning in the Mammary Gland Correlates with a Block in Lobuloalveolar Development
Mol. Endocrinol., December 1, 2002; 16(12): 2675 - 2691.
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 EndocrinologyHome page
G. J. Allan, E. Tonner, M. C. Barber, M. T. Travers, J. H. Shand, R. G. Vernon, P. A. Kelly, N. Binart, and D. J. Flint
Growth Hormone, Acting in Part through the Insulin-Like Growth Factor Axis, Rescues Developmental, But Not Metabolic, Activity in the Mammary Gland of Mice Expressing a Single Allele of the Prolactin Receptor
Endocrinology, November 1, 2002; 143(11): 4310 - 4319.
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 EndocrinologyHome page
D. S. Moons, S. Jirawatnotai, A. F. Parlow, G. Gibori, R. D. Kineman, and H. Kiyokawa
Pituitary Hypoplasia and Lactotroph Dysfunction in Mice Deficient for Cyclin-Dependent Kinase-4
Endocrinology, August 1, 2002; 143(8): 3001 - 3008.
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 J. Biol. Chem.Home page
Y. Cui, K. Miyoshi, E. Claudio, U. K. Siebenlist, F. J. Gonzalez, J. Flaws, K.-U. Wagner, and L. Hennighausen
Loss of the Peroxisome Proliferation-activated Receptor gamma (PPARgamma ) Does Not Affect Mammary Development and Propensity for Tumor Formation but Leads to Reduced Fertility
J. Biol. Chem., May 10, 2002; 277(20): 17830 - 17835.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
M. Freemark, I. Avril, D. Fleenor, P. Driscoll, A. Petro, E. Opara, W. Kendall, J. Oden, S. Bridges, N. Binart, et al.
Targeted Deletion of the PRL Receptor: Effects on Islet Development, Insulin Production, and Glucose Tolerance
Endocrinology, April 1, 2002; 143(4): 1378 - 1385.
[Abstract] [Full Text] [PDF]

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 Biol. Reprod.Home page
N. Baran, P. A. Kelly, and N. Binart
Characterization of a Prolactin-Regulated Gene in Reproductive Tissues Usingthe Prolactin Receptor Knockout Mouse Model
Biol Reprod, April 1, 2002; 66(4): 1210 - 1218.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
D. S. Moons, S. Jirawatnotai, T. Tsutsui, R. Franks, A. F. Parlow, D. B. Hales, G. Gibori, A. T. Fazleabas, and H. Kiyokawa
Intact Follicular Maturation and Defective Luteal Function in Mice Deficient for Cyclin- Dependent Kinase-4
Endocrinology, February 1, 2002; 143(2): 647 - 654.
[Abstract] [Full Text] [PDF]

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 Endocr. Rev.Home page
N. Ben-Jonathan and R. Hnasko
Dopamine as a Prolactin (PRL) Inhibitor
Endocr. Rev., December 1, 2001; 22(6): 724 - 763.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
D. R. Grattan, J. Xu, M. J. McLachlan, I. C. Kokay, S. J. Bunn, R. C. Hovey, and H. W. Davey
Feedback Regulation of PRL Secretion Is Mediated by the Transcription Factor, Signal Transducer, and Activator of Transcription 5b
Endocrinology, September 1, 2001; 142(9): 3935 - 3940.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
C. Tessier, A. Prigent-Tessier, S. Ferguson-Gottschall, Y. Gu, and G. Gibori
PRL Antiapoptotic Effect in the Rat Decidua Involves the PI3K/Protein Kinase B-Mediated Inhibition of Caspase-3 Activity
Endocrinology, September 1, 2001; 142(9): 4086 - 4094.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
A. J. Craven, C. J. Ormandy, F. G. Robertson, R. J. Wilkins, P. A. Kelly, A. J. Nixon, and A. J. Pearson
Prolactin Signaling Influences the Timing Mechanism of the Hair Follicle: Analysis of Hair Growth Cycles in Prolactin Receptor Knockout Mice
Endocrinology, June 1, 2001; 142(6): 2533 - 2539.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
Z. B. Andrews, I. C. Kokay, and D. R. Grattan
Dissociation of Prolactin Secretion from Tuberoinfundibular Dopamine Activity in Late Pregnant Rats
Endocrinology, June 1, 2001; 142(6): 2719 - 2724.
[Abstract] [Full Text] [PDF]

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 EndocrinologyHome page
A. Prigent-Tessier, U. Barkai, C. Tessier, H. Cohen, and G. Gibori
Characterization of a Rat Uterine Cell Line, UIII Cells: Prolactin (PRL) Expression and Endogenous Regulation of PRL-Dependent Genes; Estrogen Receptor {{beta}}, {{alpha}}2-Macroglobulin, and Decidual PRL Involving the Jak2 and Stat5 Pathway
Endocrinology, March 1, 2001; 142(3): 1242 - 1250.
[Abstract] [Full Text] [PDF]

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 IOVSHome page
K. A. McClellan, F. G. Robertson, J. Kindblom, H. Wennbo, J. Törnell, B. Bouchard, P. A. Kelly, and C. J. Ormandy
Investigation of the Role of Prolactin in the Development and Function of the Lacrimal and Harderian Glands Using Genetically Modified Mice
Invest. Ophthalmol. Vis. Sci., January 1, 2001; 42(1): 23 - 30.
[Abstract] [Full Text]

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