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Reproductive Biomedicine Online Apr 2021What is the gene expression pattern of prolactin receptor (PRLR) in human pre-implantation embryos and what are its functions during the embryonic development and...
RESEARCH QUESTION
What is the gene expression pattern of prolactin receptor (PRLR) in human pre-implantation embryos and what are its functions during the embryonic development and adhesion process?
DESIGN
A total of 405 discarded human vitrified oocytes and embryos donated for research by consenting couples were used in this study. The oocytes and embryos were used to analyse PRLR expression and to evaluate the influence of prolactin (PRL) supplementation in the embryo culture medium on embryo developmental competence and viability. The rates of blastocyst development and adhesion, outgrowth area, cytoskeletal reorganization and nascent adhesion formation were compared between groups.
RESULTS
PRLR expression increased significantly after embryo compaction (P < 0.0001) and blastulation (P < 0.0001). Supplementation of the embryo culture medium with PRL did not improve the developmental rate and morphological grade. In contrast, blastocyst outgrowth was significantly increased in embryos cultured with PRL (P = 0.0004). Phosphorylation of JAK2, downstream of the prolactin receptor family, was markedly higher in the PRL-treated embryos than in embryos cultured without PRL. Furthermore, the expression of mRNAs encoding ezrin-radixin-moesin proteins and epithelial-mesenchymal transition-related genes was stimulated by the activation of PRL-JAK2 signalling. The PRL-treated embryos had higher mRNA expression of integrins than non-treated embryos, and transcriptional repression of cadherin 1 was observed after PRL treatment. More nascent adherent cells expressed focal adhesion kinase and paxillin in PRL-treated embryos than in non-treated embryos.
CONCLUSIONS
Human embryos express PRLR at the morula and blastocyst stages, and PRLR signalling stimulates blastocyst adhesion by promoting integrin-based focal adhesions and cytoskeletal organization during trophoblast outgrowth.
Topics: Embryo, Mammalian; Focal Adhesions; Humans; Oocytes; Prolactin; Receptors, Prolactin
PubMed: 33608185
DOI: 10.1016/j.rbmo.2021.01.006 -
Neuroendocrinology 2013The anterior pituitary is permanently regulated by processes of apoptosis and proliferation in order to maintain tissue homeostasis. Several factors have been implicated... (Review)
Review
The anterior pituitary is permanently regulated by processes of apoptosis and proliferation in order to maintain tissue homeostasis. Several factors have been implicated in this regulation and lately, prolactin (PRL) has been included into that list. However, since PRL is secreted by anterior pituitary lactotropes, the actual outcome of its autocrine/paracrine actions on pituitary cells has remained difficult to assess. The availability of the pure PRL receptor antagonist Del1-9-G129R-hPRL has been helpful to circumvent this problem. While PRL has been traditionally associated with increased cell proliferation, recent studies revealed that this hormone actually induces apoptosis and decreases proliferation of anterior pituitary cells, by mechanisms involving the PRL receptor. The aim of this short review is to overview our current understanding of the regulation of pituitary homeostasis by PRL. Moreover, studies involving Del1-9-G129R-hPRL have helped anticipate to what extent future treatments involving PRL receptor inhibitors may interfere with processes regulated by PRL at the central level.
Topics: Animals; Homeostasis; Humans; Pituitary Gland; Prolactin; Protein Binding; Receptors, Prolactin; Signal Transduction
PubMed: 23969780
DOI: 10.1159/000354701 -
Endocrine Reviews Aug 1991PRL and GH are hormones with a wide spectrum of actions. Specific receptors are widely distributed in a number of classical target organs, but other tissues that are not... (Review)
Review
PRL and GH are hormones with a wide spectrum of actions. Specific receptors are widely distributed in a number of classical target organs, but other tissues that are not known targets also contain measurable binding sites or receptor mRNA. The most likely explanation is that PRL and GH cause effects that have not yet been characterized in certain tissues. Cloning of the cDNAs encoding PRL and GH receptors has led to the discovery that the receptors, like the hormones themselves, form a gene family. Multiple receptor forms have been identified, including a short form, which for PRL is a membrane-bound receptor or for GH is a soluble BP, and a long form, which for both PRL and GH is a membrane-bound receptor. PRL and GH receptors, and the mRNAs encoding them, can be up- and down-regulated. GH induces an up-regulation of both GH and PRL receptors, whereas PRL stimulates an increase of only its own receptor. High concentrations of either hormone induce a homologous down-regulation of receptor expression. An assay has been developed to measure the functional activity of different forms of PRL receptor by cotransfecting a milk protein fusion gene specific to PRL coupled to a reporter-gene along with the cDNA of the PRL receptor. Although the short form represents the major form present in rat mammary gland, only the long form of receptor is able to stimulate milk protein gene transcription. For GH, increased expression of the receptor in some target cells is accompanied by a modest enhancement of the response to GH. No single second messenger mediating the action of either PRL or GH has been identified. Several potential components of the signal transduction pathways have been identified, but as yet none has clearly been shown to be able to mimic the effect of PRL or GH. Because of the wide range of biological actions associated with PRL, and the existence of various forms of PRL receptors, it is doubtful that one unifying mechanism of action will be found for this hormone. No human or animal model of a genetic defect of the PRL receptor has thus far been published. Mutations in the GH receptor gene have been demonstrated in Laron type dwarfism. Different exon deletions or point or nonsense mutations resulting in modifications in the extracellular, GH binding region of the GH receptor have been reported.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Animals; Gene Expression; Growth Hormone; Humans; Prolactin; Receptors, Prolactin; Receptors, Somatotropin; Tissue Distribution
PubMed: 1935820
DOI: 10.1210/edrv-12-3-235 -
Biochemical Society Transactions May 2001Prolactin-receptor-deficient mice are a good model in which to study the various actions of prolactin. Female homozygous knockout mice are completely infertile and show... (Review)
Review
Prolactin-receptor-deficient mice are a good model in which to study the various actions of prolactin. Female homozygous knockout mice are completely infertile and show a lack of mammary development, while hemizogotes are unable to lactate following their first pregnancy. Male and female homozygotes have markedly elevated serum prolactin levels, and in some instances pituitary hyperplasia is present. Maternal behaviour is severely affected in both hemizygous and homozygous animals. Bone formation is reduced in young animals and in adults (males and females). Finally, older males and females show a slight reduction in body weight, which seems to be due to reduced abdominal fat deposition in the knockout animals.
Topics: Animals; Anxiety; Body Weight; Bone Development; Female; Immune System; Infertility; Lactation; Mammary Glands, Animal; Mice; Mice, Knockout; Prolactin; Receptors, Prolactin; Signal Transduction
PubMed: 11356125
DOI: 10.1042/0300-5127:0290048 -
Annals of Medicine 2004Prolactin (PRL) is one of a family of related hormones including growth hormone (GH) and placental lactogen (PL) that are hypothesized to have arisen from a common... (Review)
Review
Prolactin (PRL) is one of a family of related hormones including growth hormone (GH) and placental lactogen (PL) that are hypothesized to have arisen from a common ancestral gene about 500 million years ago. Over 300 different functions of PRL have been reported, highlighting the importance of this pituitary hormone. PRL is also synthesized by a number of extra-pituitary tissues including the mammary gland and the uterus. Most of PRL's actions are mediated by the unmodified 23 kDa peptide, however, PRL may be modified post-translation, thereby altering its biological effects. PRL exerts these effects by binding to its receptor, a member of the class I cytokine receptor super-family. This activates a number of signaling pathways resulting in the transcription of genes necessary for the tissue specific changes induced by PRL. Mouse knockout models of the major forms of the PRL receptor have confirmed the importance of PRLs role in reproduction. Further knockout models have provided insight into the importance of PRL signaling intermediates and the advent of transcript profiling has allowed the elucidation of a number of PRL target genes.
Topics: Alternative Splicing; Animals; Breast Neoplasms; Female; Humans; Male; Mammary Glands, Animal; Pituitary Gland, Anterior; Prolactin; Prostate; Prostatic Neoplasms; Receptors, Prolactin; Reproduction; Signal Transduction
PubMed: 15513293
DOI: 10.1080/07853890410033892 -
FASEB Journal : Official Publication of... Feb 2016The anterior pituitary hormone prolactin exerts important physiologic actions in the brain. However, the mechanism by which prolactin crosses the blood-brain barrier and...
The anterior pituitary hormone prolactin exerts important physiologic actions in the brain. However, the mechanism by which prolactin crosses the blood-brain barrier and enters the brain is not completely understood. On the basis of high expression of the prolactin receptor in the choroid plexus, it has been hypothesized that the receptor may bind to prolactin in the blood and translocate it into the cerebrospinal fluid (CSF). This study aimed to test this hypothesis by investigating transport of (125)I-labeled prolactin ((125)I-prolactin) into the brain of female mice in the presence and absence of the prolactin receptor (PRLR(-/-)). Peripherally administered prolactin rapidly activates brain neurons, as evidenced by prolactin-induced phosphorylation of signal transducer and activator of transcription 5 (pSTAT5) in neurons within 30 min of administration. The transport of prolactin into the brain was saturable, with transport effectively blocked only by a very high dose of unlabeled ovine prolactin. Transport was regulated, as in lactating mice with chronically elevated levels of prolactin, the rate of (125)I-prolactin transport into the brain was significantly increased compared to nonlactating controls. There was no change in the rate of (125)I-prolactin transport into the brain in PRLR(-/-) mice lacking functional prolactin receptors compared to control mice, indicating transport is independent of the prolactin receptor. These data suggest that prolactin transport into the brain involves another as yet unidentified transporter molecule. Because CSF levels of (125)I-prolactin were very low, even up to 90 min after administration, the data suggest that CSF is not the major route by which blood prolactin gains access to neurons in the brain.
Topics: Animals; Brain; Female; Male; Mice; Mice, Knockout; Neurons; Prolactin; Protein Transport; Receptors, Prolactin; STAT5 Transcription Factor
PubMed: 26567005
DOI: 10.1096/fj.15-276519 -
Cell and Tissue Research Jan 2019Among the more than 300 biological actions described for prolactin, its role in the neurogenic capacity of the hippocampus, which increases synaptogenesis and neuronal... (Review)
Review
Among the more than 300 biological actions described for prolactin, its role in the neurogenic capacity of the hippocampus, which increases synaptogenesis and neuronal plasticity, consolidates memory and acts as a neuronal protector against excitotoxicity-effects mediated through its receptors are more recently known. The detection of prolactin in the hippocampus and its receptors, specifically in the Ammon's horn and dentate gyrus, opened up a new field of study on the possible neuroprotective effect of hormones in a structure involved in learning and memory, as well as in emotional and behavioral processes. It is currently known, although controversial, that prolactin may be related to sex and age and that the hormone could be synthesized in the hippocampus itself. However, the regulatory mechanisms of changes in prolactin or in its hippocampal receptors still remain unknown. This review introduces the reader to general aspects concerning prolactin and its receptors and to what is currently known about the role prolactin plays in the brain and, in particular, in the hippocampus.
Topics: Animals; Brain; Hippocampus; Humans; Neuroprotection; Prolactin; Receptors, Prolactin; Signal Transduction
PubMed: 29806058
DOI: 10.1007/s00441-018-2858-2 -
Journal of Neuroendocrinology Nov 2020In addition to its critical role in lactation, the anterior pituitary hormone prolactin also influences a broad range of other physiological processes. In particular,...
In addition to its critical role in lactation, the anterior pituitary hormone prolactin also influences a broad range of other physiological processes. In particular, widespread expression of prolactin receptor (Prlr) in the brain has highlighted pleiotropic roles for prolactin in regulating neuronal function, including maternal behaviour, reproduction and energy balance. Research into the central actions of prolactin has predominately focused on effects on gene transcription via the canonical JAK2/STAT5; however, it is evident that prolactin can exert rapid actions to stimulate activity in specific populations of neurones. We aimed to investigate how widespread these rapid actions of prolactin are in regions of the brain with large populations of prolactin-sensitive neurones, and whether physiological state alters these responses. Using transgenic mice where the Cre-dependent calcium indicator, GCaMP6f, was conditionally expressed in cells expressing the long form of the Prlr, we monitored changes in levels of intracellular calcium ([Ca ] ) in ex vivo brain slice preparations as a surrogate marker of cellular activity. Here, we surveyed hypothalamic regions implicated in the diverse physiological functions of prolactin such as the arcuate (ARC) and paraventricular nuclei of the hypothalamus (PVN), as well as the medial preoptic area (MPOA). We observed that, in the ARC of males and in both virgin and lactating females, prolactin can exert rapid actions to stimulate neuronal activity in the majority of Prlr-expressing neurones. In the PVN and MPOA, we found a smaller subset of cells that rapidly respond to prolactin. In these brain regions, the effects we detected ranged from rapid or sustained increases in [Ca ] to inhibitory effects, indicating a heterogeneous nature of these Prlr-expressing populations. These results enhance our understanding of mechanisms by which prolactin acts on hypothalamic neurones and provide insights into how prolactin might influence neuronal circuits in the mouse brain.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Calcium Signaling; Female; Humans; Hypothalamus; Immunohistochemistry; Lactation; Male; Mice; Mice, Transgenic; Neurons; Paraventricular Hypothalamic Nucleus; Preoptic Area; Prolactin; Receptors, Prolactin
PubMed: 33034148
DOI: 10.1111/jne.12908 -
Pharmacology Research & Perspectives Feb 2022Endometriosis in an estrogen-dependent disease that is characterized by the presence of endometrial tissue outside the uterine cavity leading to pain and infertility in... (Comparative Study)
Comparative Study
Endometriosis in an estrogen-dependent disease that is characterized by the presence of endometrial tissue outside the uterine cavity leading to pain and infertility in many affected women. Highly efficient treatment options which create a hypo-estrogenic environment can cause side effects such as hot flushes and bone mass loss that are not favorable for premenopausal women. Previous work has demonstrated that increased local or systemic prolactin seems to be involved in the pathogenesis of endometriosis. Here we examined two prolactin receptor (PRLR) blocking antibodies in a murine endometriosis interna model which relies on the induction of systemic hyperprolactinemia in female SHN mice. The severity of the disease is determined by the degree of endometrial invasion into the myometrium. In this model, endometriosis was inhibited by clinical gold standards such as progestins and anti-estrogenic approaches. PRLR blockade completely inhibited endometriosis in this mouse model to the same extent as the anti-estrogen faslodex or the GnRH antagonist cetrorelix. In contrast to cetrorelix and faslodex, the PRLR antibodies did not decrease relative uterine weights and were thus devoid of anti-estrogenic effects. We therefore hypothesize that PRLR antibodies may present a novel and highly efficient treatment option for endometriosis with a good safety and tolerability profile. Clinical studies are on the way to test this hypothesis.
Topics: Animals; Antibodies; Disease Models, Animal; Endometriosis; Female; Fulvestrant; Gonadotropin-Releasing Hormone; Hormone Antagonists; Mice; Receptors, Prolactin
PubMed: 35084123
DOI: 10.1002/prp2.916 -
Journal of Neuroendocrinology Aug 2019Sensory neurones exhibit sex-dependent responsiveness to prolactin (PRL). This could contribute to sexual dimorphism in pathological pain conditions. The present study...
Sensory neurones exhibit sex-dependent responsiveness to prolactin (PRL). This could contribute to sexual dimorphism in pathological pain conditions. The present study aimed to determine the mechanisms underlying sex-dependent PRL sensitivity in sensory neurones. A quantitative reverse transcriptase-polymerase chain reaction shows that prolactin receptor (Prlr) long and short isoform mRNAs are expressed at comparable levels in female and male mouse dorsal root ganglia (DRG). In Prlr ;Rosa26 reporter mice, percentages of Prlr sensory neurones in female and male DRG are also similar. Characterisation of Prlr DRG neurones using immunohistochemistry and electrophysiology revealed that Prlr DRG neurones are mainly peptidergic nociceptors in females and males. However, sensory neurone type-dependent expression of Prlr is sex dimorphic. Thus, Prlr populations fell into three small- and two medium-large-sized sensory neuronal groups. Prlr DRG neurones are predominantly medium-large sized in males and are proportionally more comprised of small-sized sensory neurones in females. Specifically, Prlr /IB4 /CGRP neurones are four- to five-fold higher in numbers in female DRG. By contrast, Prlr /IB4 /CGRP /5HT3a /NPYR2 are predominant in male DRG. Prlr /IB4 /CGRP , Prlr /IB4 /CGRP and Prlr /IB4 /CGRP /NPYR2 neurones are evenly encountered in female and male DRG. These differences were confirmed using an independently generated single-cell sequencing dataset. Overall, we propose a novel mechanism by which sensory neurone type-dependent expression of Prlr could explain the unique sex dimorphism in responsiveness of nociceptors to PRL.
Topics: Animals; Cells, Cultured; Female; Ganglia, Spinal; Gene Expression; Male; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Receptors, Prolactin; Sex Characteristics
PubMed: 31231869
DOI: 10.1111/jne.12759