Boutin et al. (1989) isolated human prolactin receptor cDNA clones from hepatoma and breast cancer libraries by use
of a rat prolactin (PRL) receptor cDNA probe. The nucleotide sequence predicted a mature protein of 598
amino acids with a much longer cytoplasmic domain than the rat liver PRL receptor.
NCBI Summary:
Prolactin receptor; similar to murine PrLr
General function
Receptor, Cell death/survival, Anti-apoptotic
Comment
Cellular localization
Plasma membrane
Comment
Peters CA, et al 1999 Activation of PKC delta in the rat corpus luteum during
pregnancy and the potential role of prolactin signaling.
Prolactin is a potential physiological modulator of swine ovarian follicle function. Basini G 2014 et al.
Apart from the well established role of prolactin (PRL) in the control of mammary development and lactation, this hormone appears to possess a variety of physiological functions and evidence exists about its expression in many extra-pituitary sites. This experimental work was undertaken to gain knowledge about PRL and its receptor presence in the porcine antral follicle. In particular, we investigated the expression and local production of PRL in follicular fluid, theca and granulosa cells cultured in standard conditions and in hypoxia. Then, we also investigated its modulatory effect on several parameters mainly involved in granulosa cell function, namely redox status and steroidogenesis. In order to verify an involvement of PRL in the control of ovarian angiogenesis, a process strictly linked to follicle growth and development, we have verified possible PRL effects on granulosa cell production of Vascular Endothelial Growth Factor (VEGF) and nitric oxide as well as its modulatory role on the angiogenic activity of endothelial cells. Our data demonstrate that in the swine PRL is expressed in both components of the antral follicle, theca and granulosa layer, and it is produced by granulosa cells. Moreover, the hormone represents a relevant modulatory factor on key processes underlying follicular growth and development, such as steroidogenesis and angiogenesis.
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Luteolytic effect of prolactin is dependent on the degree of differentiation of luteal cells in the rat. Gayt?F et al. We studied the morphological and quantitative changes in cyclic corpora lutea (CCL) and in CL of pregnancy (CLP) during structural luteolysis. Elimination of CCL takes several cycles, and cell death occurs as successive apoptotic bursts, from 2100 h in proestrus to 1300 h in estrus. Each apoptotic burst determined a 60% decrease in the CL volume and an 80% decrease in the number of steroidogenic cells (SC). All these changes were inhibited by blocking the preovulatory prolactin (PRL) surge with bromocryptine (CB154). Neither apoptotic cells nor changes in the number of SC were found in regressing CLP from Day 21 of pregnancy to Day 2 postpartum, although there was a 50% decrease in the CLP volume and a 30% decrease in the mean cross-sectional area of SC. Treatment with CB154 on the day of parturition did not modify these regressive changes. On Day 5 postpartum, the volume of the CLP and the number of SC were equivalent in lactating rats (showing high PRL concentrations induced by pup suckling) and nonlactating noncycling rats (in which cyclicity and, therefore PRL surges, were blocked by treatment with LHRH antagonist). However, on Day 10 postpartum, the CLP volume and the number of SC were significantly decreased in lactating rats, and apoptotic cells were frequent. In postpartum cycling rats, the CLP did not show apoptotic cells on the day of the second postpartum estrus (on Day 5 postpartum), whereas on the day of the third postpartum estrus (on Day 9 postpartum), apoptotic cells were abundant. These results indicate that PRL does not induce apoptosis in the CLP before Day 5 postpartum and strongly suggest that the proapoptotic effect of PRL is dependent on the degree of differentiation of luteal cells.
Murphy BD, et al reviewed the role of prolactin as a luteotrophin.
This review summarizes evidence suggesting a direct luteotrophic role for the
hypophyseal hormone prolactin (PRL). This direct role consists of the capability
to stimulate progesterone synthesis in vitro, the capability to maintain the
membrane fluidity and receptors for luteinizing hormone and the capability to
import substrate for progesterone synthesis.
Wang C, et al reported the prolactin inhibition of estrogen production by cultured rat granulosa cells.
Expression regulated by
LH, Steroids, Growth Factors/ cytokines
Comment
Navickis RJ, et al reported the modulation of prolactin receptors in cultured rat granulosa cells
by FSH, LH and GnRH.
These in
vitro studies demonstrated that gonadotropins (FSH, LH and hCG) directly
enhanced PRL binding by granulosa cells, whereas GnRH inhibited FSH action.
Ovarian localization
Oocyte, Granulosa, Theca, Luteal cells
Comment
Shirota M, et al reported the detection of in situ localization of long form prolactin receptor
messenger RNA in lactating rats by biotin-labeled riboprobe.
In
the ovary, the PRLRL gene was expressed on the luteal cells in the newly formed
corpus luteum, granulosa cells and theca cells of follicles at various stages of
development, hypertrophied theca cells in the atretic follicle, and secondary
interstitial cells, but no signal was observed in the kidney.
Prolactin receptor mRNA expression in oocytes and preimplantation mouse embryos.
Reprod Biomed Online. 2005 .
Changes in mouse granulosa cell gene expression during early luteinization. McRae RS et al. Changes in gene expression during granulosa cell luteinization have been measured using serial analysis of gene expression (SAGE). Immature normal mice were treated with pregnant mare serum gonadotropin (PMSG) or PMSG followed, 48 h later, by human chorionic gonadotropin (hCG). Granulosa cells were collected from preovulatory follicles after PMSG injection or PMSG/hCG injection and SAGE libraries generated from the isolated mRNA. The combined libraries contained 105,224 tags representing 40,248 unique transcripts. Overall, 715 transcripts showed a significant difference in abundance between the two libraries of which 216 were significantly down-regulated by hCG and 499 were significantly up-regulated. Among transcripts differentially regulated, there were clear and expected changes in genes involved in steroidogenesis as well as clusters of genes involved in modeling of the extracellular matrix, regulation of the cytoskeleton and intra and intercellular signaling. The SAGE libraries described here provide a base for functional investigation of the regulation of granulosa cell luteinization.
Follicle stages
Antral, Preovulatory, Corpus luteum
Comment
Ben-David M, et al reported the identification of human ovarian receptors to human prolactin.
In the human, hyperprolactinemia may interfere with fertility. Human PRL was isolated from amniotic fluid, and its intact
monomeric iodinated isohormone B was prepared. Labeled PRL was incubated
with plasma membranes of either granulosa or whole follicular homogenates.
Relatively high specific binding sites were obtained. Saturation studies and
Scatchard analysis showed a single class of binding sites with high binding
affinity (Kd = 1.8 x 10(8) M) and a concentration of 7.9 x 10(-15) moles/mg
protein.
Clarke DL,et al reported prolactin receptor messenger ribonucleic acid expression in the
ovary during the rat estrous cycle.
These results indicate that the levels and locations of PRL-R
mRNA expression in the ovary, and therefore, the potential responsiveness of the
ovary to PRL, change throughout the reproductive cycle.
Telleria CM, et al 1997 reported the different forms of the prolactin receptor in the rat corpus
luteum: developmental expression and hormonal regulation in
pregnancy.
The results of this investigation have established
that: 1) the corpus luteum of pregnancy expresses both the short and long forms of
the PRL-R with the long form being more abundant; 2) the mRNA for both forms
of the PRL-R remains at constant levels throughout pregnancy but drops before
parturition; 3) the decline in PRL-R mRNA at the end of pregnancy is
accompanied by a dramatic rise in 20alpha-HSD; 4) PRL is able to increase the
expression of PRL-R mRNA; and that 5) both A kinase and tyrosine kinase
mediated pathways appear to participate in the up-regulatory mechanism involved
in PRL-R mRNA expression.
Bovine corpus luteum is an extrapituitary site of prolactin production Shibaya M, et al .
Prolactin (PRL) is known to be synthesized not only in the anterior pituitary, but also in other organs including the ovary. Among its various functions, PRL is regarded as the most important constituent of the luteotropic complex in rodents and pigs. The purpose of the present study was to determine whether PRL is produced locally in bovine corpus luteum (CL) and to determine its possible roles in CL. In the present study, we examined changes during the luteal phase in (1) the expressions of PRL and PRL receptors (long form: l-PRLR, short form: s-PRLR) in CL and (2) the localization of PRL in CL. We also measured the levels of PRL mRNA in cultured luteal cells and luteal endothelial cells. Furthermore, the effect of PRL on progesterone (P4) and prostaglandin (PG) F2alpha production by cultured bovine luteal cells was examined. Semiquantitative RT-PCR analysis revealed that the mRNAs for PRL and its two receptors, l- and s-PRLR, were expressed in all luteal stages examined. PRL mRNA expression was less in the regressed stage (days 19-21 after ovulation) than in the other stages. Both l-PRLR and s-PRLR mRNA expressions were higher in the late luteal stage (days 15-17) than in the other stages, while the ratio of l-PRLR to s-PRLR was less in the regressed stage than in the other stages. PRL mRNA was also detected in cultured luteal cells and luteal endothelial cells. PRL protein was immunohistochemically detected only in CL of the mid- and regressed stages. It was detected in smooth muscle cells of the intraluteal arterioles and endothelial cells but not in luteal cells and other cell types of CL. Exposure of cultured luteal cells obtained from mid-stage CL (days 8-12) to bovine PRL (100, 200 ng/ml) for 24 hr did not affect P4 and PGF2alpha production by the cells. The present study demonstrates for the first time the expressions of PRL and PRLR mRNA in bovine CL throughout the luteal phase. The overall results strongly suggest that the bovine CL is an extrapituitary site of PRL production. Mol. Reprod. Dev. (c) 2006 Wiley-Liss, Inc.
Phenotypes
Mutations
3 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment:Reese J, et al 2000 reported that implantation and decidualization defects in prolactin receptor (PRLR)-deficient mice are mediated by ovarian but not uterine
PRLR.
PRL and its homologs accomplish their biological effects through the PRL
receptor (PRLR). The results show that luteal P4 production via
ovarian PRLR signaling is required for implantation and early pregnancy. The
function of uterine PRLR remains unclear. However, the eventual loss of
pregnancy in P4-treated PRLR-/- mice suggests that uterine PRLR may be
essential for the support of late gestation.
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment: Effects of deletion of the prolactin receptor on ovarian gene expression. Grosdemouge I et al. Prolactin (PRL) exerts pleiotropic physiological effects in various cells and tissues, and is mainly considered as a regulator of reproduction and cell growth. Null mutation of the PRL receptor (R) gene leads to female sterility due to a complete failure of embryo implantation. Pre-implantatory egg development, implantation and decidualization in the mouse appear to be dependent on ovarian rather than uterine PRLR expression, since progesterone replacement permits the rescue of normal implantation and early pregnancy. To better understand PRL receptor deficiency, we analyzed in detail ovarian and corpora lutea development of PRLR-/- females. The present study demonstrates that the ovulation rate is not different between PRLR+/+ and PRLR-/- mice. The corpus luteum is formed but an elevated level of apoptosis and extensive inhibition of angiogenesis occur during the luteal transition in the absence of prolactin signaling. These modifications lead to the decrease of LH receptor expression and consequently to a loss of the enzymatic cascades necessary to produce adequate levels of progesterone which are required for the maintenance of pregnancy.
Species: mouse
Mutation name: None
type: targeted overexpression fertility: subfertile Comment: Prolactin Signaling through the Short Form of Its Receptor Represses Forkhead Transcription Factor FOXO3 and Its Target Gene Galt Causing a Severe Ovarian Defect. Halperin J et al. Prolactin (PRL) is a hormone with over 300 biological activities. Although the signaling pathway downstream of the long form of its receptor (RL) has been well characterized, little is known about PRL actions upon activation of the short form (RS). Here, we show that mice expressing only RS exhibit an ovarian phenotype of accelerated follicular recruitment followed by massive follicular death leading to premature ovarian failure. Consequently, RS-expressing ovaries of young adults are depleted of functional follicles and formed mostly by interstitium. We also show that activation of RS represses the expression of the transcription factor Forkhead box O3 (FOXO3) and that of the enzyme galactose-1-phosphate uridyltransferase (Galt), two proteins known to be essential for normal follicular development. Our finding that FOXO3 regulates the expression of Galt and enhances its transcriptional activity indicates that it is the repression of FOXO3 by PRL acting through RS that prevents Galt expression in the ovary and causes follicular death. Coexpression of RL with RS prevents PRL inhibition of Galt, and the ovarian defect is no longer seen in RS transgenic mice that coexpress RL, suggesting that RL prevents RS-induced ovarian impairment. In summary, we show that PRL signals through RS and causes, in the absence of RL, a severe ovarian pathology by repressing the expression of FOXO3 and that of its target gene Galt. We also provide evidence of a link between the premature ovarian failure seen in mice expressing RS and in mice with FOXO3 gene deletion as well as in human with Galt mutation.