Impact of prolactin receptor isoforms on reproduction

doi:10.1016/j.tem.2010.01.008

Trends in Endocrinology & Metabolism

Volume 21, Issue 6, June 2010, Pages 362-368

https://doi.org/10.1016/j.tem.2010.01.008 Get rights and content

Prolactin is a hormone involved in growth, development, reproduction, metabolism, water and electrolyte balance, brain and behavior, and immunoregulation. Its actions on reproductive processes represent the largest group of functions identified for this hormone. Besides the classic long form of the prolactin receptor, many short form receptors have been identified in rodents and human tissues. Mouse mutagenesis studies have offered insight into the biology of the prolactin family, providing compelling evidence that different isoforms have independent biological activity. The possibility that short forms mediate cell proliferation is important for a variety of tissues including mammary glands and ovarian follicles. This review summarizes the current knowledge about prolactin signaling and its role in reproduction through either long or short isoform receptors.

Section snippets

Actions of prolactin

Prolactin (PRL) is a polypeptide hormone originally identified by its ability to stimulate mammary gland development and lactation. More than 300 separate actions have been reported in various vertebrates, including effects on water and salt balance, growth and development, endocrinology and metabolism, brain and behavior, reproduction, and immune regulation and protection [1]. Although there is evidence indicating that PRL acts as an autocrine, paracrine and endocrine progression factor for

Sites of synthesis and control of prolactin secretion

PRL is produced predominantly by the lactotropic cells of the anterior pituitary gland. However, it is also generated in extrapituitary sites such as immune, decidual, mammary, epithelial and fat cells 7, 8, 9. Its secretion is under dual regulation by hypothalamic hormones via the pituitary portal circulation 4, 10. The predominant regulatory signal is the inhibition of prolactin secretion by the neurotransmitter, dopamine. Evidence suggests that prolactin secretion is regulated by three

Signaling pathways activated by PRL through long and short forms

The biological effects of prolactin are mediated by its interaction with PRL receptor (PRLR), a member of the cytokine receptor superfamily 1, 2. The hormone in its tertiary structure is composed of a bundle of four antiparallel α-helices [13] and uses a conserved, single-pass transmembrane receptor classified as a cytokine type 1 receptor. The receptor is devoid of intrinsic tyrosine kinase activity but can be phosphorylated by associated proteins.

PRLRs are present in nearly all organs and

Expression of different PRLR isoforms

Expression of the various receptor isoforms varies during development and as a function of the stage of the estrous cycle, pregnancy and lactation in rodents. The long-R is strongly expressed in the ovary, adrenal, kidney, mammary gland, small intestine, choroid plexus and pancreas, but other organs (e.g. liver), also express high levels of the short-R. However, because of the broad distribution of PRLR, it is difficult to propose a general overview of its expression regulation [1]. The various

Phenotypic characterization of mouse models

A large body of literature attests that lactogenic hormones [40] including placental lactogens and prolactin (Box 1) play roles in rodent reproductive function. One of the best established functions of PRL in reproductive function in rodents is its key role in maintaining the ovarian corpus luteum (CL) and progesterone production through the long-R, because this form is predominantly expressed 41, 42. Several key functions for PRL have been clarified from studies of transgenic and knockout

Phenotype of PRLR^−/− mice

PRL^−/−[43] and PRLR^−/−[44] female mice on a mixed 129Sv/C57Bl6 background were first described as completely infertile, and the same observation was confirmed later on a pure background [45]. After mating with males of established fertility, no litters were produced even though each female mated repeatedly at regular intervals. PRLR^−/− ovaries in both backgrounds are normal and there are no differences in either follicular development or ovulation and fertilization rate compared with wild-type

Phenotype of mice with over-expression of one short isoform of the PRLR (PRLR^−/− short-R mice)

Whereas PRL regulation of CL is thought to be through activation of the long-R, the effect of short-R activation on ovarian development is not known. To examine the putative role of the short-R in vivo, we generated PRLR^−/− female mice that express only the PR-1 short isoform [61].

PRLR^−/− short-R mice treated with hCG produce a significantly greater number of oocytes during ovulation than do either PRLR^−/− or wild-type mice. The number of secondary, pre-antral and antral follicles is markedly

Signaling molecules regulated through the short PRLR isoform

PRL signals through the short-R in the ovary and actively regulates expression of several genes identified by microarray analysis [61]. Interestingly, Galt, whose mutation induces galactosemia [65], is downregulated in PRLR^−/− short-R ovaries. In fact, Galt expression is completely abolished in ovaries of PRLR^−/− short-R females, in contrast to their PRLR^−/− littermates (Figure 2).

The mouse Galt promoter sequence contains 16 putative forkhead transcription factor sites, five of them being FOXO3

Prolactin and reproductive medicine in women

In normal individuals, circulating serum prolactin is thought to reflect almost entirely pituitary PRL secretion [10]; however, it is possible that other, extrapituitary sources also contribute to local tissue PRL levels.

Unlike in rodents, the role of PRL in human ovarian function is unclear, in large part because no disruptive mutations of human PRL or the human PRLR have been identified. Moreover, the increase in prolactin levels observed in pathological hyperprolactinaemia results in

Concluding remarks

The studies described in this review confirm and extend the data of Das and Vonderhaar [78], who demonstrated a mitogenic response in vitro to the PRL short-R. Whether these results are a result of different intrinsic activities of the various short forms of the PRLR or to different model systems used, they are clearly worthy of further investigation. Although it is not yet clear how PRL signals in the human ovary, signalling pathways induced by prolactin through its short-R should be an

Acknowledgements

We thank M. Freemark for helpful comments and would like to acknowledge current and former members of our laboratory for their valuable contributions and discussions. This work was supported by the Institut National de la Santé et de la Recherche Médicale and Fondation pour la Recherche Médicale.

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Women experience chronic pain more often than men with some pain conditions being specific to women while others are more prevalent in women. Prolactin, a neuropeptide hormone with higher serum levels in women, has recently been demonstrated in preclinical studies to sensitize nociceptive sensory neurons in a sexually dimorphic manner. Dysregulation of prolactin and prolactin receptors may be responsible for increased pain especially in female predominant conditions such as migraine, fibromyalgia, and pelvic pain. In this review, we focus on the role of prolactin in endometriosis, a condition characterized by pelvic pain and infertility that affects a large proportion of women during their reproductive age. We discuss the symptoms and pathology of endometriosis and discuss how different sources of prolactin secretion may contribute to this disease. We highlight our current understanding of prolactin-mediated mechanisms of nociceptor sensitization in females and how this mechanism may apply to endometriosis. Lastly, we report the results of a systematic review of clinical studies conducted by searching the PubMed and EMBASE databases to identify association between endometriosis and blood levels of prolactin. The results of this search strongly indicate that serum prolactin levels are increased in patients with endometriosis and support the possibility that high levels of prolactin may promote pelvic pain in these patients and increase vulnerability to other comorbid pain conditions likely by dysregulating prolactin receptor expression. Targeting of prolactin and prolactin receptors may improve management of pain associated with endometriosis.
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The classical PRL (PRL1) is best known for its role in enabling female mammals to produce milk. However, it is influential over a large number of functions; more than 300 separate actions of PRL1 have been reported in various vertebrates. Control of water and salt balance is an important function, especially in teleost fish. PRL1 universally acts in an endocrine, autocrine, and paracrine manner through the PRL receptor (PRLR) that belongs to the class I cytokine receptor family. PRL1 has important cell turnover-related functions and acts as growth, differentiating, and antiapoptotic factors, especially in hematopoiesis, angiogenesis, and the immune system through several pathways. PRL2 is structurally related to PRL1 and is able to activate PRLR; however, the function of PRL2 is largely unknown.
Effects of milking frequency and domperidone injections on milk production and prolactin signaling in the mammary gland of dairy cows
2020, Journal of Dairy Science
Eleven mid-lactation Holstein cows were milked twice daily during the first 2 experimental weeks. During wk 3 to 10, the cows were differentially milked: right quarters were milked thrice daily (3×) and left quarters were milked once daily (1×). During wk 11 to 14, all quarters were milked twice daily. After 4 wk of differential milking, the cows received daily i.m. injections of the dopamine antagonist domperidone (DOMP; 300 mg; n = 6) or of dimethyl sulfoxide as the control (CTL; n = 5) for 8 wk (wk 7–14). During the differential milking period (wk 3–6), milk production was greater for quarters milked 3× than for those milked 1× but did not differ between DOMP and CTL cows. During the differential milking + injection period (wk 7–10), milk production continued to differ according to milking frequency. However, DOMP injection did not have an effect or interact with milking frequency on milk production. During the injection period (wk 11–14), milk production remained greater in the quarters previously milked 3× and milk production increased in DOMP injected cows but not in CTL cows. Injections of DOMP increased prolactin concentration, which was greater in the serum of DOMP cows than in that of CTL cows during the differential milking + injection and the injection periods. The expression of genes that are directly related to milk synthesis (CSN2, LALBA, and ACACA) was greater in the 3× quarters than in the 1× quarters. In addition, DOMP increased CSN2 expression during the injection period. The expression of both isoforms of the PRLR gene was greater in the 3× quarters during the differential milking + injection and the injection periods. At the protein level, injections of DOMP tended to increase the number of long PRLR isoform during the differential milking + injection period. The number of short PRLR isoform was greater in the 1× quarters than in the 3× quarters during the differential milking, the differential milking + injection, and the injection periods. The total amount of STAT3 protein was greater in the 1× quarters during the differential milking and the differential milking + injection periods. The amount of phosphorylated STAT3 protein was greater in the 1× quarters during the differential milking period. The total amount of phosphorylated STAT5 protein was greater in the 3× quarters during the differential milking and the differential milking + injection periods. The results of this experiment support the hypothesis that the responsiveness of the mammary gland to PRL is modulated by milking frequency, although the underlying mechanism remains to be determined.
Morphological and functional adaptations of pancreatic alpha-cells during late pregnancy in the mouse
2020, Metabolism: Clinical and Experimental
Citation Excerpt :
In addition to the potential in vivo interactions described above that may take place during pregnancy, the results obtained with the alpha-cell line also point to a direct role of PL and PRL in the dual actions on alpha-cells during gestation. Activation of the PRL receptor involves the stimulation of at least three main signaling pathways in the pancreatic beta-cell and other cell types: JAK2/STAT5, MAPK and PI3K [1,44]. In the case of mouse alpha-cells and alpha-TC1 cells, activation of the PI3K pathway has been associated with both the inhibition of glucagon secretion [6,30] and the increase of proliferation [56].
Pregnancy represents a major metabolic challenge for the mother, and involves a compensatory response of the pancreatic beta-cell to maintain normoglycemia. However, although pancreatic alpha-cells play a key role in glucose homeostasis and seem to be involved in gestational diabetes, there is no information about their potential adaptations or changes during pregnancy.
Non-pregnant (controls) and pregnant C57BL/6 mice at gestational day 18.5 (G18.5) and their isolated pancreatic islets were used for in vivo and ex vivo studies, respectively. The effect of pregnancy hormones was tested in glucagon-secreting α-TC1.9 cells. Immunohistochemical analysis was performed in pancreatic slices. Glucagon gene expression was monitored by RT-qPCR. Glucagon secretion and plasma hormones were measured by ELISA.
Pregnant mice on G18.5 exhibited alpha-cell hypertrophy as well as augmented alpha-cell area and mass. This alpha-cell mass expansion was mainly due to increased proliferation. No changes in alpha-cell apoptosis, ductal neogenesis, or alpha-to-beta transdifferentiation were found compared with controls. Pregnant mice on G18.5 exhibited hypoglucagonemia. Additionally, in vitro glucagon secretion at low glucose levels was decreased in isolated islets from pregnant animals. Glucagon content was also reduced. Experiments in α-TC1.9 cells indicated that, unlike estradiol and progesterone, placental lactogens and prolactin stimulated alpha-cell proliferation. Placental lactogens, prolactin and estradiol also inhibited glucagon release from α-TC1.9 cells at low glucose levels.
The pancreatic alpha-cell in mice undergoes several morphofunctional changes during late pregnancy, which may contribute to proper glucose homeostasis. Gestational hormones are likely involved in these processes.
Effectiveness of absorption and passage through the small intestine, as a model of oral prolactin administration
2019, Biomedicine and Pharmacotherapy
The process of absorption and permeation of PRL through the small intestine of 1-day-old piglet from the different compositions of solutions prepared for oral administration was investigated. This was achieved by determining the effect of hormone concentration (0.25 mg / ml or 0.5 mg / ml or 0.75 mg / ml), the concentration of stabilizing substances - trehalose (6 mg / ml or 12 mg / ml or 18 mg / ml) and mannitol (6 mg / ml or 12 mg / ml or 18 mg / ml) and the pH of the solution (2.5 or 3.0 or 3.5) on the degree of absorption and permeation of the PRL. The conditions for the absorption and penetration of PRL from solutions of various compositions for oral administration through the natural membrane (small intestine of the 1-day-old sucking piglet) in the in vivo conditions were simulated. The studies used an in vivo model in which the enzymatic profile in the body is not yet fully developed (no pepsin).
It was found that in the studied range the absorption of PRL in the small intestine of the 1-day-old sucking piglet is significantly related to the concentration of the hormone and trehalose in the solution from which it is absorbed. In contrast, all factors studied (hormone concentration, trehalose and mannitol concentration, pH value of the solution) influence the process of penetration of the PRL in the studied range. It was also found that the hormone concentration significantly influences the rate of its absorption and permeation (the fastest occurs at a concentration of 0.5 mg/mL). The results suggest possibility of oral prolactin administration in order to ensure proper growth, development and increase the resistance and survival of sucking piglets.
Candidate genes associated with reproductive traits in rabbits
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Trends in Endocrinology & Metabolism

ReviewImpact of prolactin receptor isoforms on reproduction

Section snippets

Actions of prolactin

Sites of synthesis and control of prolactin secretion

Signaling pathways activated by PRL through long and short forms

Expression of different PRLR isoforms

Phenotypic characterization of mouse models

Phenotype of PRLR−/− mice

Phenotype of mice with over-expression of one short isoform of the PRLR (PRLR−/− short-R mice)

Signaling molecules regulated through the short PRLR isoform

Prolactin and reproductive medicine in women

Concluding remarks

Acknowledgements

Trends Endocrinol. Metab.

J. Biol. Chem.

Brain Res.

Adv. Protein Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Am. J. Pathol.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Trends Endocrinol. Metab.

Curr. Top. Dev. Biol.

FEBS Lett.

Mol. Cell Endocrinol.

Reprod. Toxicol.

Fertil. Steril.

Prolactin and its receptor: actions, signal transduction pathways and phenotypes observed in prolactin receptor knockout mice

Endocr. Rev.

The role of prolactin in mammary carcinoma

Endocr. Rev.

Prolactin: a pleiotropic neuroendocrine hormone

J. Neuroendocrinol.

Null mutation of prolactin receptor gene produces a defect in maternal behavior

Endocrinology

Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin

Science

Extrapituitary prolactin: distribution, regulation, functions, and clinical aspects

Endocr. Rev.

LS14: a novel human adipocyte cell line that produces prolactin

Endocrinology

Prolactin: structure, function, and regulation of secretion

Physiol. Rev.

Control of the estradiol-induced prolactin surge by the suprachiasmatic nucleus

Endocrinology

Expression of multiple forms of the prolactin receptor

Mol. Endocrinol.

Multiple new isoforms of the human prolactin receptor gene

Adv. Exp. Med. Biol.

Model for growth hormone receptor activation based on subunit rotation within a receptor dimer

Nat. Struct. Mol. Biol.

Ovine placental lactogen-induced heterodimerization of ovine growth hormone and prolactin receptors in living cells is demonstrated by fluorescence resonance energy transfer microscopy and leads to prolonged phosphorylation of signal transducer and activator of transcription (STAT)1 and STAT3

Endocrinology

Unmodified prolactin (PRL) and S179D PRL-initiated bioluminescence resonance energy transfer between homo- and hetero-pairs of long and short human PRL receptors in living human cells

Mol. Endocrinol.

Ligand-independent homo- and hetero-dimerization of human prolactin receptor variants: inhibitory action of the short forms by heterodimerization

Mol. Endocrinol.

Ligand-Independent dimerization of the human prolactin receptor isoforms: functional implications

Mol. Endocrinol.

Prolactin: the new biology of an old hormone

Annu. Rev. Physiol.

Regulation of prolactin receptor levels and activity in breast cancer

J. Mammary. Gland Biol. Neoplasia.

PRL activates the cyclin D1 promoter via the Jak2/Stat pathway

Mol. Endocrinol.

PTP1D is a positive regulator of the prolactin signal leading to b-casein promoter activation

EMBO J.

Comparison of long and short forms of the prolactin receptor on prolactin induced milk protein gene transcription

Proc. Natl. Acad. Sci. U. S. A.

Review
Impact of prolactin receptor isoforms on reproduction

Phenotype of PRLR^−/− mice

Phenotype of mice with over-expression of one short isoform of the PRLR (PRLR^−/− short-R mice)