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David R Grattan - One of the best experts on this subject based on the ideXlab platform.
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Neuroendocrine Mechanisms Governing Sex Differences in Hyperalgesic Priming Involve Prolactin Receptor Sensory Neuron Signaling.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2020Co-Authors: Candler Paige, David R Grattan, Vincent Goffin, Priscilla A. Barba-escobedo, Jennifer Mecklenburg, Mayur J. Patil, Gregory Dussor, Armen N. Akopian, Theodore J. PriceAbstract:Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the Prolactin Receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using ΔPRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female, but not male, mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling.SIGNIFICANCE STATEMENT Females are more likely to experience chronic pain than males, but the mechanisms that underlie this sex difference are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice, where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that Prolactin Receptor expression in Nav1.8+ neurons was necessary for hyperalgesic priming in female, but not male, mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal Prolactin Receptor.
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neuroendocrine mechanisms governing sex differences in chronic pain involve Prolactin Receptor sensory neuron signaling
bioRxiv, 2020Co-Authors: Candler Paige, David R Grattan, Vincent Goffin, Jennifer Mecklenburg, Mayur J. Patil, Gregory Dussor, Armen N. Akopian, Priscilla A Barbaescobedo, Theodore J. PriceAbstract:Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the Prolactin Receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female but not male mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling. SIGNIFICANCE STATEMENT: Females are more likely to experience chronic pain than males, but the mechanisms that underlie this sexual dimorphism are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice, where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that Prolactin Receptor expression in Nav1.8+ neurons was necessary for hyperalgesic priming in female, but not male mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal Prolactin Receptor.
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widespread cell specific Prolactin Receptor expression in multiple murine organs
Endocrinology, 2019Co-Authors: Mari Aoki, David R Grattan, Philipp Wartenberg, Ramona Grunewald, Hollian R Phillipps, Amanda Wyatt, Ulrich BoehmAbstract:The Prolactin Receptor (Prlr) mediates not only the multiple effects of Prolactin, but also those of the placental lactogens and, in humans, some actions of growth hormone. Although Prlr expression has been reported to be widespread in the body, specific cellular expression patterns within tissues are undefined for many organs. One persisting problem in investigating Prlr function is that the protein is difficult to detect using conventional methods. To allow investigation of Prlr expression with a single cell resolution, we have recently developed a knock-in mouse strain in which Cre recombinase is expressed together with the long isoform of the Prlr using an internal ribosome entry site. When crossed to a Cre-dependent reporter mouse strain, Cre-mediated recombination will genetically label cells that acutely express the Prlr as well as cells that have transiently expressed the Prlr during development. We report here the anatomical distribution of cells which express the fluorescent reporter τ green fluorescent protein in a total of 38 organs prepared from young adult male and female Prlr reporter mice. Our results establish a resource for dissecting the functional role of Prlr in multiple murine tissues.
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Elevated Prolactin during Pregnancy Drives a Phenotypic Switch in Mouse Hypothalamic Dopaminergic Neurons
Elsevier, 2019Co-Authors: Siew H. Yip, David R Grattan, Ilona C Kokay, Nicola Romanò, Papillon Gustafson, David J. Hodson, Eloise J. Williams, Agnes O. Martin, Patrice Mollard, Stephen J. BunnAbstract:Summary: Altered physiological states require neuronal adaptation. In late pregnancy and lactation, a sub-population of the mouse hypothalamic tuberoinfundibular dopaminergic (TIDA) neurons alters their behavior to synthesize and release met-enkephalin rather than dopamine. These neurons normally release dopamine to inhibit Prolactin secretion and are activated by Prolactin in a short-loop feedback manner. In lactation, dopamine synthesis is suppressed in an opioid-dependent (naloxone-reversible) manner, meaning that Prolactin secretion is disinhibited. Conditional deletion of the Prolactin Receptor in neurons reveals that this change in phenotype appears to be driven by Prolactin itself, apparently through an alteration in intracellular signaling downstream of the Prolactin Receptor that favors enkephalin production instead of dopamine. Thus, Prolactin effectively facilitates its own secretion, which is essential for lactation and maternal behavior. These studies provide evidence of a physiologically important, reversible alteration in the behavior of a specific population of hypothalamic neurons in the adult brain. : Pituitary Prolactin secretion is inhibited by dopamine released by hypothalamic neurons. Yip et al. show that, during lactation, these TIDA neurons alter their response to Prolactin and release enkephalin in place of dopamine. This mechanism promotes rather than inhibits Prolactin secretion, supporting its elevation during lactation. Keywords: Prolactin, Prolactin Receptor, dopamine, encephalin, hypothalamus, tuberoinfundibular dopaminergic neurons, neuronal plasticity, lactation, lactotroph
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identification of Prolactin sensitive gaba and kisspeptin neurons in regions of the rat hypothalamus involved in the control of fertility
Endocrinology, 2011Co-Authors: Ilona C Kokay, Sandra L Petersen, David R GrattanAbstract:Prolactin Receptor mRNA is expressed in GABA and kisspeptin neurons in the rostral hypothalamus but in relatively few GnRH neurons, suggesting that hyperProlactinemia might cause infertility through actions on afferent inputs to GnRH neurons.
Vincent Goffin - One of the best experts on this subject based on the ideXlab platform.
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Neuroendocrine Mechanisms Governing Sex Differences in Hyperalgesic Priming Involve Prolactin Receptor Sensory Neuron Signaling.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2020Co-Authors: Candler Paige, David R Grattan, Vincent Goffin, Priscilla A. Barba-escobedo, Jennifer Mecklenburg, Mayur J. Patil, Gregory Dussor, Armen N. Akopian, Theodore J. PriceAbstract:Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the Prolactin Receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using ΔPRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female, but not male, mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling.SIGNIFICANCE STATEMENT Females are more likely to experience chronic pain than males, but the mechanisms that underlie this sex difference are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice, where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that Prolactin Receptor expression in Nav1.8+ neurons was necessary for hyperalgesic priming in female, but not male, mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal Prolactin Receptor.
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neuroendocrine mechanisms governing sex differences in chronic pain involve Prolactin Receptor sensory neuron signaling
bioRxiv, 2020Co-Authors: Candler Paige, David R Grattan, Vincent Goffin, Jennifer Mecklenburg, Mayur J. Patil, Gregory Dussor, Armen N. Akopian, Priscilla A Barbaescobedo, Theodore J. PriceAbstract:Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the Prolactin Receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female but not male mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling. SIGNIFICANCE STATEMENT: Females are more likely to experience chronic pain than males, but the mechanisms that underlie this sexual dimorphism are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice, where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that Prolactin Receptor expression in Nav1.8+ neurons was necessary for hyperalgesic priming in female, but not male mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal Prolactin Receptor.
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structural motifs in the extracellular domain of the Prolactin Receptor govern fold and functionality
Receptors and clinical investigation, 2015Co-Authors: Vincent Goffin, Chi Zhang, Patrick England, Isabelle Broutin, Birthe B KragelundAbstract:The Prolactin Receptor (PRLR) is an archetype cytokine Receptor. It is a single-pass transmembrane Receptor with limited complexity that is devoid of enzyme activity. Intracellular signaling involves various Receptor-associated kinases including Jak2, Erk1/2, Src and Akt. As the PRLR is emerging as a relevant target in Oncology the understanding of the molecular basis of its activation is crucial. In the frame of an inter-disciplinary consortium involving biophysicists, structural biologists and cell biologists, we have successfully combined complementary approaches such as optical and nuclear magnetic resonance spectroscopic analyses, X-ray crystallography, surface plasmon resonance and cell-based assays to start elucidate the structural features of ligand-Receptor interaction. However, the features of the PRLR extracellular domain (ECD) that participate in the transmission of the hormonal message across the cell membrane and/or in selective activation of intracellular signaling cascades remained uncharacterized. In two recently published studies, we identified residues 146 and 170 as two key residues of the PRLR-ECD that control critical Receptor properties including basal signaling activity, ligand sensitivity, species specificity, folding, stability and Receptor turnover. These two residues are in close proximity of each other in the membrane proximal domain of the PRLR-ECD and participate in a network of interactions with other residues, in particular within a specific residue quartet. Strikingly, these residues are involved in, or close to, the Receptor dimerization interface, suggesting that their mechanism of action may involve structural reorientation of the Receptor chains that are necessary to (selectively) disseminate the signal from the ECD to the intracellular domain. The identification of such residues in this and other cytokine Receptors should affect future structure-directed drug development strategies aimed at providing pathway-selective treatment strategies.
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A Residue Quartet in the Extracellular Domain of the Prolactin Receptor Selectively Controls Mitogen-activated Protein Kinase Signaling
Journal of Biological Chemistry, 2015Co-Authors: Chi Zhang, Florence Boutillon, Marie Bernadet, Mads Nygaard, Gitte Haxholm, Sylviane Hoos, Patrick England, Isabelle Broutin, Birthe Kragelund, Vincent GoffinAbstract:Cytokine Receptors elicit several signaling pathways, but it is poorly understood how they select and discriminate between them. We have scrutinized the Prolactin Receptor as an archetype model of homodimeric cytokine Receptors to address the role of the extracellular membrane proximal domain in signal transfer and pathway selection. Structure-guided manipulation of residues involved in the Receptor dimerization interface identified one residue (position 170) that in cell-based assays profoundly altered pathway selectivity and species-specific bio-characteristics. Subsequent in vitro spectroscopic and nuclear magnetic resonance analyses revealed that this residue was part of a residue quartet responsible for specific local structural changes underlying these effects. This included alteration of a novel aromatic T-stack within the membrane proximal domain, which promoted selective signaling affecting primarily the MAPK (ERK1/2) pathway. Importantly, activation of the MAPK pathway correlated with in vitro stabilities of ternary ligand·Receptor complexes, suggesting a threshold mean lifetime of the complex necessary to achieve maximal activation. No such dependence was observed for STAT5 signaling. Thus, this study establishes a residue quartet in the extracellular membrane proximal domain of homodimeric cytokine Receptors as a key regulator of intracellular signaling discrimination.
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the wsxws motif in cytokine Receptors is a molecular switch involved in Receptor activation insight from structures of the Prolactin Receptor
Structure, 2012Co-Authors: Robert Dagil, Vincent Goffin, Maiken J Knudsen, J G Olsen, Charlotte Oshea, Magnus Franzmann, Kaare Teilum, Jens BreinholtAbstract:Summary The Prolactin Receptor (PRLR) is activated by binding of Prolactin in a 2:1 complex, but the activation mechanism is poorly understood. PRLR has a conserved WSXWS motif generic to cytokine class I Receptors. We have determined the nuclear magnetic resonance solution structure of the membrane proximal domain of the human PRLR and find that the tryptophans of the motif adopt a T-stack conformation in the unbound state. By contrast, in the hormone bound state, a Trp/Arg-ladder is formed. The conformational change is hormone-dependent and influences the Receptor-Receptor dimerization site 3. In the constitutively active, breast cancer-related Receptor mutant PRLR I146L , we observed a stabilization of the dimeric state and a change in the dynamics of the motif. Here we demonstrate a structural link between the WSXWS motif, hormone binding, and Receptor dimerization and propose it as a general mechanism for class 1 Receptor activation.
Paul A Kelly - One of the best experts on this subject based on the ideXlab platform.
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development and potential clinical uses of human Prolactin Receptor antagonists
Endocrine Reviews, 2005Co-Authors: Vincent Goffin, Paul A Kelly, Sophie Bernichtein, Philippe TouraineAbstract:There is a large body of literature showing that Prolactin (PRL) exerts growth-promoting activities in breast cancer, and possibly in prostate cancer and prostate hyperplasia. In addition, increasing evidence argues for the involvement of locally produced (autocrine) PRL, perhaps even more than pituitary-secreted (endocrine) PRL, in tumor growth. Because dopamine analogs are unable to inhibit PRL production in extrapituitary sites, alternative strategies need investigation. To that end, several PRL Receptor antagonists have been developed by introducing various mutations into its natural ligands. For all but one of these analogs, the mechanism of action involves a competition with endogenous PRL for Receptor binding. Such compounds are thus candidates to counteract the undesired actions of PRL, not only in tumors, but also in dopamine-resistant Prolactinomas. In this review, we describe the different versions of antagonists that have been developed, with emphasis on the controversies regarding their characterization, and the limits for their potential development as a drug. The most recently developed antagonist, Delta1-9-G129R-hPRL, is the only one that is totally devoid of residual agonistic activity, meaning it acts as pure antagonist. We discuss to what extent this new molecule could be considered as a lead compound for inhibiting the actions of human PRL in the above-mentioned diseases. We also speculate on the multiple questions that could be addressed with respect to the therapeutic use of PRL Receptor antagonists in patients.
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immune system development and function in Prolactin Receptor deficient mice
Journal of Immunology, 1999Co-Authors: Brigitte Bouchard, Christopher J Ormandy, J P Di Santo, Paul A KellyAbstract:Prolactin (PRL) is the primary lactogenic pituitary hormone that plays an essential role in many aspects of reproduction, from fertilization to mammary gland development and maternal behavior. PRL has also been reported to play a role in immunoregulation. Because initial observations indicated that hypophysectomized rats present abnormalities of the immune system, including increased thymic atrophy and lymphopenia, a number of studies have focused on the potential immunomodulatory roles of PRL. This hormone exerts its biological activities following binding to specific cell surface PRL Receptors (PRLRs). In this report, we have characterized the development and function of the immune system in PRLR-deficient mice. Compared with wild-type control mice, PRLR −/− mice demonstrate no alterations in thymic or splenic cellularity or in the composition of the lymphocyte subsets present in primary (bone marrow and thymus) or secondary (spleen and lymph nodes) lymphoid organs. Lymphocytes from PRLR −/− mice are functional in vitro, as they can proliferate normally to mitogens, cytokines, and allogeneic cells. PRLR −/− splenocytes display normal NK-mediated cytotoxicity to YAC-1 target cells. In vivo studies have revealed that PRLR −/− mice are able to 1) generate normal steady-state Ig levels, 2) mount a normal specific Ig response following immunization with a T-dependent Ag, 3) eliminate injected allogeneic tumor cells, and 4) effectively control Listeria monocytogenes infection. Taken together, these results show that immune system development and function proceed normally in the absence of PRL-mediated signaling and suggest that PRLR pathways are not essential for immunomodulation in vivo.
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Prolactin controls mammary gland development via direct and indirect mechanisms
Developmental Biology, 1999Co-Authors: Cathrin Brisken, Nadine Binart, Paul A Kelly, Sarabjeet Kaur, Tony E Chavarria, Robert L Sutherland, Robert A Weinberg, Christopher J OrmandyAbstract:The inactivation of the Prolactin Receptor gene by homologous recombination has made it possible to investigate the role of Prolactin signaling in mammary gland development without resort to ablative surgery of the endocrine glands. In knockout mice lacking the Prolactin Receptor, mammary development is normal up to puberty. Subsequently, the ducts branch less frequently than those of wild-type animals. While terminal end buds differentiate to alveolar buds in wild-type females by the end of puberty, in knockout females terminal end bud-like structures persist at the ductal ends. To distinguish between the developmental defects that are intrinsic to the epithelium and those that result from systemic endocrine alterations in Prolactin Receptor knockout mice, mammary epithelium from Prolactin Receptor knockouts was transplanted into mammary fat pads of wild-type mice. In virgin mice, the knockout epithelial transplants developed normally at puberty, indicating an indirect effect of Prolactin on ductal development. Prolactin Receptor knockout females are infertile due to multiple reproductive defects, but epithelial transplants allowed us to assess the extent to which the absence of Prolactin Receptor is limiting, under systemic conditions that allow full mammary gland development. During pregnancy, the Prolactin Receptor knockout transplants showed normal side branching and the formation of alveolar buds, but no lobuloalveolar development. Thus, Prolactin affects mammary morphogenesis in two different ways: it controls ductal side branching and terminal end bud regression in virgin animals via indirect mechanisms, but acts directly on the mammary epithelium to produce lobuloalveolar development during pregnancy.
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the growth hormone Prolactin Receptor family
Recent Progress in Hormone Research, 1993Co-Authors: Paul A Kelly, Jean Djiane, Marc Edery, Sajid Ali, M Rozakis, L Goujon, M Nagano, I Pellegrini, D Gould, Joelle FinidoriAbstract:Publisher Summary This chapter provides an overview of growth hormone (GH) and Prolactin Receptor (PRL) family. Sequence analysis has confirmed that GH and PRL have selected regions of strong homology and, along with placental lactogen (PL) or chorionic somatotropin (CS), form a family of polypeptide hormones that appear to have arisen by the duplication of an ancestral gene. Hormones act by first binding to a specific Receptor on or inside the cell. Two general classes of hormone Receptors exist, namely, DNA binding Receptors and membrane Receptors. The events responsible for the transfer of the hormonal message inside the cell occur just after the interaction of the ligand with the Receptor; they remain, for the most part, unknown. In mammals, PRL is primarily responsible for the development of the mammary gland and lactogenesis. The best known effects of PRL are in mammary epithelial cells. PRL acts in association with insulin and glucocorticoids to stimulate milk protein gene expression at both the transcriptional and posttranscriptional levels, because the rate of gene transcription and the stability of milk protein mRNAs are increased under the influence of the hormone. GH, on the other hand, has a direct action on the differentiation of preadipocytes, where it is necessary for the initiation of the differentiation program for cells to become responsive to insulin-like growth factor-I and for its mitogenic effect.
Nadine Binart - One of the best experts on this subject based on the ideXlab platform.
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impact of Prolactin Receptor isoforms on reproduction
Trends in Endocrinology and Metabolism, 2010Co-Authors: Nadine Binart, Anne Bachelot, Justine BouillyAbstract: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.
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Prolactin Receptor Signaling Is Essential for Perinatal Brown Adipocyte Function: A Role for Insulin-like Growth Factor-2.
PLoS ONE, 2008Co-Authors: Say Viengchareun, Marc Lombès, Nathalie Servel, Bruno Fève, Michael Freemark, Nadine BinartAbstract:BACKGROUND: The lactogenic hormones Prolactin (PRL) and placental lactogens (PL) play central roles in reproduction and mammary development. Their actions are mediated via binding to PRL Receptor (PRLR), highly expressed in brown adipose tissue (BAT), yet their impact on adipocyte function and metabolism remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: PRLR knockout (KO) newborn mice were phenotypically characterized in terms of thermoregulation and their BAT differentiation assayed for gene expression studies. Derived brown preadipocyte cell lines were established to evaluate the molecular mechanisms involved in PRL signaling on BAT function. Here, we report that newborn mice lacking PRLR have hypotrophic BAT depots that express low levels of adipocyte nuclear Receptor PPARgamma2, its coactivator PGC-1alpha, uncoupling protein 1 (UCP1) and the beta3 adrenoceptor, reducing mouse viability during cold challenge. Immortalized PRLR KO preadipocytes fail to undergo differentiation into mature adipocytes, a defect reversed by reintroduction of PRLR. That the effects of the lactogens in BAT are at least partly mediated by Insulin-like Growth Factor-2 (IGF-2) is supported by: i) a striking reduction in BAT IGF-2 expression in PRLR KO mice and in PRLR-deficient preadipocytes; ii) induction of cellular IGF-2 expression by PRL through JAK2/STAT5 pathway activation; and iii) reversal of defective differentiation in PRLR KO cells by exogenous IGF-2. CONCLUSIONS: Our findings demonstrate that the lactogens act in concert with IGF-2 to control brown adipocyte differentiation and growth. Given the prominent role of brown adipose tissue during the perinatal period, our results identified Prolactin Receptor signaling as a major player and a potential therapeutic target in protecting newborn mammals against hypothermia.
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Prolactin controls mammary gland development via direct and indirect mechanisms
Developmental Biology, 1999Co-Authors: Cathrin Brisken, Nadine Binart, Paul A Kelly, Sarabjeet Kaur, Tony E Chavarria, Robert L Sutherland, Robert A Weinberg, Christopher J OrmandyAbstract:The inactivation of the Prolactin Receptor gene by homologous recombination has made it possible to investigate the role of Prolactin signaling in mammary gland development without resort to ablative surgery of the endocrine glands. In knockout mice lacking the Prolactin Receptor, mammary development is normal up to puberty. Subsequently, the ducts branch less frequently than those of wild-type animals. While terminal end buds differentiate to alveolar buds in wild-type females by the end of puberty, in knockout females terminal end bud-like structures persist at the ductal ends. To distinguish between the developmental defects that are intrinsic to the epithelium and those that result from systemic endocrine alterations in Prolactin Receptor knockout mice, mammary epithelium from Prolactin Receptor knockouts was transplanted into mammary fat pads of wild-type mice. In virgin mice, the knockout epithelial transplants developed normally at puberty, indicating an indirect effect of Prolactin on ductal development. Prolactin Receptor knockout females are infertile due to multiple reproductive defects, but epithelial transplants allowed us to assess the extent to which the absence of Prolactin Receptor is limiting, under systemic conditions that allow full mammary gland development. During pregnancy, the Prolactin Receptor knockout transplants showed normal side branching and the formation of alveolar buds, but no lobuloalveolar development. Thus, Prolactin affects mammary morphogenesis in two different ways: it controls ductal side branching and terminal end bud regression in virgin animals via indirect mechanisms, but acts directly on the mammary epithelium to produce lobuloalveolar development during pregnancy.
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null mutation of the Prolactin Receptor gene produces multiple reproductive defects in the mouse
Genes & Development, 1997Co-Authors: Christopher J Ormandy, Marc Edery, A Camus, Jacqueline Barra, Diane Damotte, B Lucas, Helene Buteau, N Brousse, Charles Babinet, Nadine BinartAbstract:Mice carrying a germ-line null mutation of the Prolactin Receptor gene have been produced by gene targeting in embryonic stem cells. Heterozygous females showed almost complete failure of lactation attributable to greatly reduced mammary gland development after their first, but not subsequent, pregnancies. Homozygous females were sterile owing to a complete failure of embryonic implantation. Moreover, they presented multiple reproductive abnormalities, including irregular cycles, reduced fertilization rates, defective preimplantation embryonic development, and lack of pseudopregnan cy. Half of the homozygous males were infertile or showed reduced fertility. This work establishes the Prolactin Receptor as a key regulator of mammalian reproduction, and provides the first total ablation model to further study the role of the Prolactin Receptor and its ligands.
Jean Djiane - One of the best experts on this subject based on the ideXlab platform.
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Developmental Expression and Localization of the Prolactin Receptor (PRL-R) Gene in Ewe Mammary Gland during Pregnancy and Lactation: Estimation of the Ratio of the Two Forms of PRL-R Messenger Ribonucleic Acid'
2016Co-Authors: Jean DjianeAbstract:In this study, we have analyzed the developmental expression of the Prolactin Receptor (PRL-R) gene in the ewe mammary gland during pregnancy and lactation. Using Northern and slot-blot analysis and in situ hybridization, we showed that the level of PRL-R mRNA in mammary epithelial cells increased during the second half of pregnancy, decreased at the end of pregnancy, and remained relatively stable during lactation with a level above that observed at the beginning of pregnancy. As shown by RNase protection assay, the ratio of the long to the short form of the PRL-R mRNA was always above 1. This ratio increased between Day 70 of pregnancy and term and decreased progres-sively during lactation. The high level of PRL-R mRNA before the induction of a,,-casein gene expression suggests that PRL may be involved in the growth and development of the mammary gland. More precisely, the increase of the ratio of the long to the short form of the PRL-R during lactogenesis suggests that the latter form may have a dominant negative action in the activa-tion of milk protein gene transcription. Thus the long/short-form ratio of the PRL-R may play a key role in the shift between growth and differentiation of the mammary gland
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recombinant Prolactin Receptor extracellular domain of rainbow trout oncorhynchus mykiss subcloning preparation and characterization
General and Comparative Endocrinology, 2000Co-Authors: Yael Sandowski, Jean Djiane, Yael Cohen, Le P Rouzic, Ch Bignon, Francoise Rentierdelrue, Patrick Prunet, Arieh GertlerAbstract:Abstract The cDNA of the extracellular domain of rainbow trout ( Oncorhynchus mykiss ) Prolactin Receptor (trPRLR-ECD) was cloned in the prokaryotic expression vector pMON to enable its expression in Escherichia coli after induction with nalidixic acid. The bacterially expressed trPRLR-ECD protein, contained within the refractile body pellet, was solubilized in 4.5 M urea, refolded, and purified on a Q-Sepharose column, pH 8, by stepwise elution with NaCl. The bioactive monomeric 26-kDa fraction was eluted in 0.2 M NaCl, yielding 20 mg/2.5 L of induced culture. The purified protein was over 98% homogeneous, as shown by SDS–PAGE in the presence or absence of reducing agent and by chromatography on a Superdex column. Binding experiments using [ 125 I]ovine placental lactogen (oPL) as a ligand revealed that human growth hormone (hGH), oPL, and ovine Prolactin (oPRL) were the most effective competitors, with respective IC 50 values of 1.32, 2.27, and 2.70 nM. Chicken (ch) PRL did not compete at all, and homologous trPRL was much less effective, with a corresponding IC 50 value of 1826 nM. Gel-filtration was used to determine the stoichiometry of trPRLR-ECD's interaction with oPL, hGH, and oPRL. Only oPL yielded a 2:1 complex, whereas hGH and oPRL formed only 1:1 complexes, with excess trPRLR-ECD being seen at the initial 2:1 trPRLR-ECD:hGH or trPRLR-ECD:oPRL ratios. No studies were performed with chPRL because of its inability to compete with [ 125 I]oPL or with trPRL because of its low affinity toward trPRLR-ECD. The present results agree with previous findings indicating, as in mammals, that homologous PRL interacts transiently with its Receptor and suggest that transient homologous PRL-induced homodimerization of the Receptor is sufficient to initiate a biological signal, despite the fact that, in classical binding experiments, only low specific binding can be detected.
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Prolactin signal transduction to milk protein genes carboxy terminal part of the Prolactin Receptor and its tyrosine phosphorylation are not obligatory for jak2 and stat5 activation
Molecular and Cellular Endocrinology, 1997Co-Authors: Olivier Goupille, Nathalie Daniel, Christophe Bignon, Genevieve Jolivet, Jean DjianeAbstract:Abstract In this study, we have developed several Chinese Hamster ovary (CHO) cell clones stably expressing various deletion mutant forms of the rabbit Prolactin Receptor (rbPRL-R) to better define the domains of the Receptor involved in JAK2 kinase interaction, STAT5 activation, and to assess the role of tyrosine phosphorylation of the PRL-R in signal transduction. We observed that the box 1 region of the Receptor was critical for productive interaction with JAK2 and its tyrosine phosphorylation after PRL stimulation. However, this region appeared to require the presence of additional cytoplasmic domain region(s), such as box 2, to exert its complete effect. In addition, we found that a mutant form lacking the 141 C-terminal residues lost the capacity to be tyrosine phosphorylated in response to PRL but remained able to activate JAK2 kinase and STAT5 transcription factor, indicating that it contained the minimal sequence required for STAT5 activation. The absence of tyrosine phosphorylation of this C-terminal rbPRL-R mutant upon PRL stimulation indicated that the phosphorylation of the PRL-R normally occured in the last 141 animo acids (aa) containing three tyrosines and was not absolutely necessary for induction of these early events in PRL signal transduction. Transfectant cell lines expressing wild type (WT) PRL-R and this C-terminal mutant form were able to induce CAT activity upon PRL stimulation when transiently transfected with the ovine-β-lactoglobulin promoter, containing STAT5 recognition sites, fused to the CAT reporter gene. The comparison between transcriptional activity of these two Receptor forms leads to the conclusion that the C-terminal region of the rbPRL-R, containing the physiological sites for tyrosine phosphorylation, is probably responsible for an amplification of the PRL signal to milk protein genes.
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interaction of lactogenic hormones with purified recombinant extracellular domain of rabbit Prolactin Receptor expressed in insect cells
FEBS Letters, 1993Co-Authors: Arieh Gertler, Barbara Petridou, Gwen G Kriwi, Jean DjianeAbstract:Abstract The extracellular domain of rabbit Prolactin Receptor (rbPRLR-ECD) expressed in an insect/baculovirus expression system was purified by affinity chromatography on immobilized PRL followed by gel filtration. The purified protein was over 90% homogeneous as indicated by SDS-PAGE in the presence or absence of reducing agent, and by chromatography on a Superdex column. Its molecular mass determined by SDS-PAGE was 32 kDa, and by gel filtration, 27 kDa. Both values are higher than the 22.8 kDa deduced from the cDNA sequence, indicating extensive glycosylation. The Ka value for interaction with ovine (o) PRL was 25.4 nM−1, but even at high rbPRLR-ECD:hormone molar ratios, the stoichiometry of interaction with oPRL or human growth hormone indicated formation of only 1:1 complexes, in contrast to human growth hormone (hGH)-ECD which forms 2:1 complexes with hGH.
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the growth hormone Prolactin Receptor family
Recent Progress in Hormone Research, 1993Co-Authors: Paul A Kelly, Jean Djiane, Marc Edery, Sajid Ali, M Rozakis, L Goujon, M Nagano, I Pellegrini, D Gould, Joelle FinidoriAbstract:Publisher Summary This chapter provides an overview of growth hormone (GH) and Prolactin Receptor (PRL) family. Sequence analysis has confirmed that GH and PRL have selected regions of strong homology and, along with placental lactogen (PL) or chorionic somatotropin (CS), form a family of polypeptide hormones that appear to have arisen by the duplication of an ancestral gene. Hormones act by first binding to a specific Receptor on or inside the cell. Two general classes of hormone Receptors exist, namely, DNA binding Receptors and membrane Receptors. The events responsible for the transfer of the hormonal message inside the cell occur just after the interaction of the ligand with the Receptor; they remain, for the most part, unknown. In mammals, PRL is primarily responsible for the development of the mammary gland and lactogenesis. The best known effects of PRL are in mammary epithelial cells. PRL acts in association with insulin and glucocorticoids to stimulate milk protein gene expression at both the transcriptional and posttranscriptional levels, because the rate of gene transcription and the stability of milk protein mRNAs are increased under the influence of the hormone. GH, on the other hand, has a direct action on the differentiation of preadipocytes, where it is necessary for the initiation of the differentiation program for cells to become responsive to insulin-like growth factor-I and for its mitogenic effect.
