DOCSLIB.ORG

Long Isoform of Prolactin Receptor Predominates in Rat Intrahepatic Bile Ducts and Further Increases Under Obstructive Cholestasis

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Long Isoform of Prolactin Receptor Predominates in Rat Intrahepatic Bile Ducts and Further Increases Under Obstructive Cholestasis 345 Long isoform of prolactin receptor predominates in rat intrahepatic bile ducts and further increases under obstructive cholestasis R L Bogorad, T Y Ostroukhova, A N Orlova, P M Rubtsov1 and O V Smirnova Laboratory of Endocrinology, Faculty of Biology, Lomonosov Moscow State University, Vorob’ev Hills, 119992, Moscow, Russian Federation 1Laboratory of Hormones and Receptors, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova Str., 119991, Moscow, Russian Federation (Requests for offprints should be addressed to R L Bogorad; Email: [email protected]) Abstract Prolactin participates in the regulation of liver function. bromocriptine-treated animals. Common bile-duct However, prolactin receptor (PrlR) expression and its ligation was used as the experimental model of regulation have been described only for hepatocytes. In cholestasis. Our results demonstrate that the expression this study, we investigated the expression and regulation pattern and regulation of PrlR isoforms is totally of PrlR isoforms in the other important intrahepatic different in cholangiocytes compared with hepato- cellular compartment: the biliary epithelial cells, or cytes: (1) mature rat cholangiocytes express low levels cholangiocytes. Our aim was to determine whether of PrlR, while it is very high in hepatocytes, (2) only prolactin should be considered as a potential regulator the long isoform is detected in cholangiocytes, while of cholangiocyte function under normal and pathologi- the short isoform predominates in hepatocytes and (3) cal conditions. Cholangiocytes and hepatocytes were PrlR levels in cholangiocytes are induced by obstructive differentially isolated from rat liver. PrlR expression was cholestasis, but not by sex hormones or prolactin, while analysed at the mRNA level by isoform-specific it is the opposite in hepatocytes. From these data, the semiquantitative PCR, and at the protein level by actions of prolactin on liver are anticipated to exhibit immunostaining of liver sections. Hormonal regulation strong cell-type specificity in both normal and of PrlR expression was evaluated by comparing pathological conditions. intact rats with gonadectomized, pituitary-grafted or Journal of Endocrinology (2006) 188, 345–354 Introduction STAT activation, resulting from formation of short and long PrlR heterodimers (Perrot-Applanat et al. 1997). Several prolactin receptor (PrlR) isoforms have been However, short PrlR is also involved in transduction of identified in mammals. In rat, they have been shown to be specific signals, including activation of serine/threonine produced via alternative splicing of PrlR pre-mRNA: the protein kinase cascades and interaction with 17-hydroxy- formation of long and short isoforms result from alterna- steroid dehydrogenase (Das & Vonderhaar 1995, Duan tive inclusion of proximal exon 10 or distal exon 11 into et al. 1997, Nikelainen et al. 1998). the mature mRNA, respectively (Bole-Feysot et al. 1998). Liver is very specific compared with other organs with These receptor isoforms differ in length and structure of respect to PrlR expression: the level of PrlR is higher than their intracellular domain, which affects signalling prop- in most other tissues, and this mainly involves the short erties. Thus, tissue sensitivity and responsiveness to pro- isoform since the long PrlR is 10% of total (Nagano & lactin depend on both the level of total PrlR expression Kelly 1994). The total level of PrlR in hepatocytes is and the ratio of short to long isoforms. regulated by sex hormones: oestrogens increase and Prolactin signalling is initiated by formation of a com- androgens decrease the content of PrlR mRNA and plex involving one prolactin molecule and two molecules protein (Jolicoeur et al. 1989, Sakaguchi et al. 1994). As in of PrlR. The long PrlR isoform activates various signalling other tissues, prolactin was shown to be another positive cascades, among which Janus kinase/signal transduction regulator of PrlR expression in the liver (Baxter & and activators of transcription (JAK/STAT) is considered Zaltsman 1984, Bogorad et al. 2000). Although PrlR to be the central pathway (Bole-Feysot et al. 1998). The expression is well documented, the actions of prolactin in short PrlR isoform exerts dominant-negative effects on liver remain poorly understood (Bole-Feysot et al. 1998). Journal of Endocrinology (2006) 188, 345–354 DOI: 10.1677/joe.1.06468 0022–0795/06/0188–345 2006 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/26/2021 09:48:06AM via free access 346 R L BOGORAD and others · Prolactin receptors in rat cholangiocytes Relatively few disembodied data were published regard- according to Alpini et al. (1989). In order to elevate the ing prolactin effects on hepatocyte proliferation (Picolleti circulating prolactin level some rats were subjected to et al. 1997) as well as on expression of a number of transplantation of two donor pituitaries into kidney hepatocyte proteins (Bole-Feysot et al. 1998, Liu et al. capsule. The completeness of graft acceptance was deter- 1992). No liver phenotype has been reported in prolactin- mined for each animal by autopsy. This well-characterized or PrlR-knockout mice (Horseman et al. 1997, Ormandy impact increases the prolactin level approximately 5-fold, et al. 1997), which does not exclude compensatory actions to 55 ng/ml (Garcia et al. 2003). In 2 days recipient by other cytokine receptors. animals underwent CBDL. Although liver consists essentially of hepatocytes, Bromocriptine was injected daily after CBDL as 50% another important cell compartment involves intrahepatic ethanol suspension of bromocriptine pills (Gedeon biliary epithelial cells, referred to as cholangiocytes. These Richter, Budapest, Hungary; 10 µg/kg animal weight) to cells are organized in a three-dimensional network of decrease the level of circulating prolactin. Vehicle was ducts, which implies interactions with other hepatic cell injected into control animals. This treatment decreases types. Despite their relatively small number, cholangio- the prolactin level 10-fold, to approximately 1 ng/ml cytes play an essential role in liver functions, including bile (Bogorad et al. 2000). formation and secretion (Alpini et al. 1994b). The pro- The tissues were subjected to simultaneous isolation of portion and activity of these two cell types can change bile-duct units and hepatocytes or fixed in 4% paraform dramatically depending on the conditions. During hepatic and used for immunohistochemical staining. diseases, such as obstructive cholestasis or jaundice, All animal groups were compared with the correspond- the bile tree grows intensively, and the proportion of ing sham-operated group to control for non-specific cholangiocytes can be increased to up to 20% of total effects. The preliminary reverse transcriptase (RT)-PCR liver cells (Alpini et al. 1994a). The responsiveness of experiments did not reveal any influence of sham opera- cholangiocytes to various regulatory factors is also mark- tions on PrlR mRNA level or ratio of PrlR isoforms in edly enhanced under cholestatic conditions (Alpini et al. cholangiocytes (one-way analysis of variance (ANOVA), 1994b, Alvaro et al. 2000b). Because prolactin participates P>0·6; data not shown). in the regulation of water–ion balance and secretory processes (Bole-Feysot et al. 1998), its involvement in the regulation of cholangiocyte function is expected. How- Immunohistochemistry and cytophotometry ever, since evidence is still lacking that these cells express Tissues were embedded in paraplast and sliced into 3 µm PrlR, any effect of prolactin under normal or pathological sections. Immunohistochemical staining of sections with states remains speculative. These issues were addressed in anti-PrlR antibodies (clone U5; provided by Dr V Goffin our study. We report the profile of expression on both and Dr P Kelly, INSERM, Paris, France) and cyto- long and short PrlR isoforms in rat liver, under normal photometry were done as described previously (Bogorad and cholestatic conditions. We also provide some clues on et al. 2000). One hundred and fifty cells on two tissue their regulation by sex hormones and prolactin. The sections of each animal were measured for the intensity of unexpected conclusion of our investigations is that the PrlR-positive immunostaining, which is represented as expression of PrlR isoforms and their regulation in optical density (OD). cholangiocytes and hepatocytes are dramatically different, and in many cases opposite. Simultaneous isolation of bile-duct units and hepatocytes In some experiments, the rat livers were subjected to Materials and Methods isolation of hepatocytes and cholangiocytes as intrahepatic bile-duct units (Mennone et al. 1995). Briefly, the liver Animals was perfused by Ca2+-/Mg2+-free Hanks’ balanced salts All animals were housed on standard rodent chow and solution (all reagents and enzymes for cell isolation and tap water ad libitum and received humane care, the reagents for tissues preparations were from Sigma) study protocols complied with the Faculty of Biology’s containing 0·7 mM EDTA, then perfused through the (Lomonosov Moscow State University) guidelines. portal vein by collagenase (0·05%) in Hanks’ balanced salts Intact mature 12-week-old male and female rats as well solution with 40 mM HEPES and 5 mM CaCl2. Residual as immature rats were used to determine the parameters of portal tissue was mechanically dissociated
Load more

Recommended publications
  • Distress Regulates Different Pathways in the Brain of Common Carp: a Preliminary Study
    animals Communication Distress Regulates Different Pathways in the Brain of Common Carp: A Preliminary Study Alexander Burren and Constanze Pietsch * School of Agricultural, Forest and Food Sciences (HAFL), Applied University Berne (BFH), 3052 Zollikofen, Switzerland; [email protected] * Correspondence: [email protected] Simple Summary: The aquaculture sector provides for nearly half of the world’s seafood consump- tion, thanks to its large expansion over the last 30 years. Despite this intense growth, clear guidelines for responsible practices and animal wellbeing are lacking. Gene expression studies are a fundamen- tal tool for understanding welfare, but stress-markers in aquaculture fish species are poorly studied. In addition, the biostatistical analysis of gene expression data is not trivial, and this study applies different statistical methods in order to evaluate potential differences in the gene expression levels between control fish and fish acutely stressed by exposure to air. Abstract: In this study, a stress trial was conducted with common carp, one of the most important species in aquaculture worldwide, to identify relevant gene regulation pathways in different areas of the brain. Acute distress due to exposure to air significantly activated the expression of the immediate early gene c-fos in the telencephalon. In addition, evidence for regulation of the two corticotropin-releasing factor (crf ) genes in relation to their binding protein (corticotropin-releasing hormone-binding protein, crh-bp) is presented in this preliminary study. Inferences on the effects Citation: Burren, A.; Pietsch, C. of due to exposure to air were obtained by using point estimation, which allows the prediction of Distress Regulates Different a single value.
    [Show full text]
  • Relaxin: a Missing Link in the Pathomechanisms of Systemic Lupus Erythematosus?
    http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2014; 24(4): 547–551 © 2014 Japan College of Rheumatology DOI: 10.3109/14397595.2013.844297 REVIEW ARTICLE Relaxin: A missing link in the pathomechanisms of Systemic Lupus Erythematosus? Madhusoothanan Bhagavathi Perumal1 and Saranya Dhanasekaran2 1 Queensland Brain Institute, The University of Queensland, Brisbane, Australia and 2 Chhatrapati Shahuji Maharaj Hospital, Lucknow, India Downloaded from https://academic.oup.com/mr/article/24/4/547/6303646 by guest on 01 October 2021 Abstract Keywords Systemic Lupus Erythematosus (SLE) is an autoimmune rheumatic disease which predominantly Autoimmunity , Endometrium , Macrophages , aff ects women of reproductive age. Despite signifi cant progress in recent years to elucidate Relaxin , Systemic Lupus Erythematosus many potential mechanisms involved in the generation of autoimmunity the factors behind the high incidence among women, the relapsing – remitting clinical course and pregnancy-related History complications in SLE remain unclear. In this review, we hypothesize a potential role for uterine Received 5 February 2013 endometrium through its production of relaxin, a peptide hormone, as a “ missing-link ” to explain Accepted 15 May 2013 this female predominance, variable clinical course and obstetric complications operating in SLE. Published online 16 October 2013 Background In contrast, M2 macrophages are important in tissue repair and wound healing. They express high levels of anti-infl ammatory Systemic Lupus Erythematosus (SLE) is an autoimmune disease cytokines (such as IL10) as well as growth factors such as vascular which can aff ect any part of the body leading to a myriad of clini- endothelial growth factor (VEGF) and basic Fibroblast growth fac- cal manifestations.
    [Show full text]
  • Supplementary Table 2
    Supplementary Table 2. Differentially Expressed Genes following Sham treatment relative to Untreated Controls Fold Change Accession Name Symbol 3 h 12 h NM_013121 CD28 antigen Cd28 12.82 BG665360 FMS-like tyrosine kinase 1 Flt1 9.63 NM_012701 Adrenergic receptor, beta 1 Adrb1 8.24 0.46 U20796 Nuclear receptor subfamily 1, group D, member 2 Nr1d2 7.22 NM_017116 Calpain 2 Capn2 6.41 BE097282 Guanine nucleotide binding protein, alpha 12 Gna12 6.21 NM_053328 Basic helix-loop-helix domain containing, class B2 Bhlhb2 5.79 NM_053831 Guanylate cyclase 2f Gucy2f 5.71 AW251703 Tumor necrosis factor receptor superfamily, member 12a Tnfrsf12a 5.57 NM_021691 Twist homolog 2 (Drosophila) Twist2 5.42 NM_133550 Fc receptor, IgE, low affinity II, alpha polypeptide Fcer2a 4.93 NM_031120 Signal sequence receptor, gamma Ssr3 4.84 NM_053544 Secreted frizzled-related protein 4 Sfrp4 4.73 NM_053910 Pleckstrin homology, Sec7 and coiled/coil domains 1 Pscd1 4.69 BE113233 Suppressor of cytokine signaling 2 Socs2 4.68 NM_053949 Potassium voltage-gated channel, subfamily H (eag- Kcnh2 4.60 related), member 2 NM_017305 Glutamate cysteine ligase, modifier subunit Gclm 4.59 NM_017309 Protein phospatase 3, regulatory subunit B, alpha Ppp3r1 4.54 isoform,type 1 NM_012765 5-hydroxytryptamine (serotonin) receptor 2C Htr2c 4.46 NM_017218 V-erb-b2 erythroblastic leukemia viral oncogene homolog Erbb3 4.42 3 (avian) AW918369 Zinc finger protein 191 Zfp191 4.38 NM_031034 Guanine nucleotide binding protein, alpha 12 Gna12 4.38 NM_017020 Interleukin 6 receptor Il6r 4.37 AJ002942
    [Show full text]
  • Galanin and Prolactin in 2 Cichlids 2021.Pdf
    General and Comparative Endocrinology 309 (2021) 113785 Contents lists available at ScienceDirect General and Comparative Endocrinology journal homepage: www.elsevier.com/locate/ygcen Research paper Galanin and prolactin expression in relation to parental care in two sympatric cichlid species from Lake Tanganyika Filipa Cunha-Saraiva a,*, Rute S.T. Martins b, Deborah M. Power b, Sigal Balshine c,1, Franziska C. Schaedelin a,1 a Konrad Lorenz Institute of Ethology, Department of Interdisciplinary Life Sciences, University of Veterinary Medicine Vienna, Austria b Centre of Marine Sciences (CCMAR), University of Algarve, Faro, Portugal c Aquatic Behavioural Ecology Laboratory, Department of Psychology, Neuroscience, & Behaviour, McMaster University, Ontario, Canada ARTICLE INFO ABSTRACT Keywords: Our understanding of the hormonal mechanisms underlying parental care mainly stems from research on species Gene expression with uniparental care. Far less is known about the physiological changes underlying motherhood and fatherhood Breeding cycle in biparental caring species. Here, using two biparental caring cichlid species (Neolamprologus caudopunctatus and Neurogenomic mechanisms Neolamprologus pulcher), we explored the relative gene-expression levels of two genes implicated in the control of Cooperative breeding parental care, galanin (gal) and prolactin (prl). We investigated whole brain gene expression levels in both, male Biparental care Neolamprologus caudopunctatus and female caring parents, as well as in non-caring individuals of both species. Caring males had higher prl and Neolamprologus pulcher gal mRNA levels compared to caring females in both fsh species. Expression of gal was highest when young were mobile and the need for parental defense was greatest and gal was lowest during the more stationary egg tending phase in N.
    [Show full text]
  • Co-Regulation of Hormone Receptors, Neuropeptides, and Steroidogenic Enzymes 2 Across the Vertebrate Social Behavior Network 3 4 Brent M
    bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Co-regulation of hormone receptors, neuropeptides, and steroidogenic enzymes 2 across the vertebrate social behavior network 3 4 Brent M. Horton1, T. Brandt Ryder2, Ignacio T. Moore3, Christopher N. 5 Balakrishnan4,* 6 1Millersville University, Department of Biology 7 2Smithsonian Conservation Biology Institute, Migratory Bird Center 8 3Virginia Tech, Department of Biological Sciences 9 4East Carolina University, Department of Biology 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 1 bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Running Title: Gene expression in the social behavior network 2 Keywords: dominance, systems biology, songbird, territoriality, genome 3 Corresponding Author: 4 Christopher Balakrishnan 5 East Carolina University 6 Department of Biology 7 Howell Science Complex 8 Greenville, NC, USA 27858 9 [email protected] 10 2 bioRxiv preprint doi: https://doi.org/10.1101/435024; this version posted October 4, 2018. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
    [Show full text]
  • Suppression of Breast Cancer by Small Molecules That Block the Prolactin Receptor
    cancers Article Suppression of Breast Cancer by Small Molecules That Block the Prolactin Receptor Dana C. Borcherding 1,† , Eric R. Hugo 1,† , Sejal R. Fox 1, Eric M. Jacobson 2, Brian G. Hunt 1, Edward J. Merino 3 and Nira Ben-Jonathan 1,* 1 Department of Cancer Biology, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA; [email protected] (D.C.B.); [email protected] (E.R.H.); [email protected] (S.R.F.); [email protected] (B.G.H.) 2 Department of Internal Medicine, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA; [email protected] 3 Department of Chemistry, University of Cincinnati, Cincinnati, OH 45267, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-513-558-4821; Fax: +1-513-558-4823 † Contributed equally to this investigation as first authors. Simple Summary: Unabated tumor growth, metastasis, and resistance to hormone therapy and/or to chemotherapy constitute serious impediments for combating breast cancer (BC). With the exception of targeted anti-HER2/neu therapy and combination therapies, there have been no radical changes in the standard of care for BC patients in the past two decades. In addition, there are only limited options for treating BC-derived brain metastases that cause high morbidity and mortality. This report describes the use of high throughput screening (HTS) for identifying novel small molecules that blocked the prolactin receptor (PRLR) and suppressed BC in a laboratory setting. These small Citation: Borcherding, D.C.; Hugo, molecules have a great potential to become effective therapeutics in patients with BC.
    [Show full text]
  • A Role for Placental Kisspeptin in Β Cell Adaptation to Pregnancy
    A role for placental kisspeptin in β cell adaptation to pregnancy James E. Bowe, … , Stephanie A. Amiel, Peter M. Jones JCI Insight. 2019;4(20):e124540. https://doi.org/10.1172/jci.insight.124540. Research Article Endocrinology Reproductive biology During pregnancy the maternal pancreatic islets of Langerhans undergo adaptive changes to compensate for gestational insulin resistance. Kisspeptin has been shown to stimulate insulin release, through its receptor, GPR54. The placenta releases high levels of kisspeptin into the maternal circulation, suggesting a role in modulating the islet adaptation to pregnancy. In the present study we show that pharmacological blockade of endogenous kisspeptin in pregnant mice resulted in impaired glucose homeostasis. This glucose intolerance was due to a reduced insulin response to glucose as opposed to any effect on insulin sensitivity. A β cell–specific GPR54-knockdown mouse line was found to exhibit glucose intolerance during pregnancy, with no phenotype observed outside of pregnancy. Furthermore, in pregnant women circulating kisspeptin levels significantly correlated with insulin responses to oral glucose challenge and were significantly lower in women with gestational diabetes (GDM) compared with those without GDM. Thus, kisspeptin represents a placental signal that plays a physiological role in the islet adaptation to pregnancy, maintaining maternal glucose homeostasis by acting through the β cell GPR54 receptor. Our data suggest reduced placental kisspeptin production, with consequent impaired kisspeptin-dependent β cell compensation, may be a factor in the development of GDM in humans. Find the latest version: https://jci.me/124540/pdf RESEARCH ARTICLE A role for placental kisspeptin in β cell adaptation to pregnancy James E.
    [Show full text]
  • THE ROLE of RELAXIN in PROSTATE CANCER by VANESSA
    THE ROLE OF RELAXIN IN PROSTATE CANCER by VANESSA CAMILLE THOMPSON B.Sc, The University of Victoria, 2001 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Genetics) THE UNIVERSITY OF BRITISH COLUMBIA July 2007 © Vanessa Camille Thompson, 2007 Abstract Prostate cancer is the leading cause of cancer in men, and there is currently a lack of novel treatment options for this disease. Relaxin, part of the insulin superfamily, is a potent peptide hormone normally produced and secreted by the human prostate. cDNA and tissue microarray analyses, indicated that relaxin is highly overexpressed in prostate cancer progression to androgen independence (Al), and is negatively regulated by androgens. Characterization of the relaxin receptor, LGR7, in xenografts and human patient tissue microarrays (TMAs) indicated that LGR7 is expressed in the stroma and epithelia, suggesting that relaxin may act in an autocrine and/or paracrine fashion. Relaxin is known to increase angiogenesis through upregulation of vascular endothelial growth factor, and matrix metalloproteases. To elucidate novel pathways that may be upregulated by relaxin in prostate cancer, the effects of relaxin overexpression in the LNCaP prostate cancer xenograft model were analysed by gene expression microarrays. A novel discovery is that the protocadherinY (PCDHY)/Wnt pathway is upregulated by relaxin, resulting in P-catenin translocation from the cell membrane to the cytoplasm and upregulation of Wntll, which can stimulate proliferation, transformation, and migration. Relaxin is well characterized in the uterus and ovary to increase insulin-like growth factor-I (IGF-I); relaxin may also increase IGF-I in prostate cancer.
    [Show full text]
  • From Galactorrhea to Osteopenia: Rethinking Serotonin– Prolactin Interactions
    Neuropsychopharmacology (2004) 29, 833–846 & 2004 Nature Publishing Group All rights reserved 0893-133X/04 $25.00 www.neuropsychopharmacology.org From Galactorrhea to Osteopenia: Rethinking Serotonin– Prolactin Interactions ,1,2 1,3 Ana BF Emiliano* and Julie L Fudge 1 2 Department of Psychiatry, University of Rochester Medical Center, Rochester, NY, USA; Department Medicine, University of Rochester Medical 3 Center, Rochester, NY, USA; and Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, NY, USA The widespread use of the selective serotonin reuptake inhibitors (SSRIs) has been accompanied by numerous reports describing a potential association with hyperprolactinemia. Antipsychotics are commonly known to elevate serum prolactin (PRL) through blockade of dopamine receptors in the pituitary. However, there is little awareness of the mechanisms by which SSRIs stimulate PRL release. Hyperprolactinemia may result in overt symptoms such as galactorrhea, which may be accompanied by impaired fertility. Long-term clinical sequelae include decreased bone density and the possibility of an increased risk of breast cancer. Through literature review, we explore the possible pathways involved in serotonin-induced PRL release. While the classic mechanism of antipsychotic-induced hyperprolactinemia directly involves dopamine cells in the tuberoinfundibular pathway, SSRIs may act on this system indirectly through GABAergic neurons. Alternate pathways involve serotonin stimulation of vasoactive intestinal peptide (VIP) and oxytocin (OT) release. We conclude with a comprehensive review of clinical sequelae associated with hyperprolactinemia, and the potential role of SSRIs in this phenomenon. Neuropsychopharmacology (2004) 29, 833–846, advance online publication, 3 March 2004; doi:10.1038/sj.npp.1300412 Keywords: hyperprolactinemia; fertility; bone density; breast cancer; vasoactive intestinal peptide; SSRI INTRODUCTION only beginning to be investigated (Klibanski et al, 1980; Wang et al, 2002).
    [Show full text]
  • Y4 Receptor Knockout Rescues Fertility in Ob/Ob Mice
    Downloaded from genesdev.cshlp.org on October 6, 2021 - Published by Cold Spring Harbor Laboratory Press Y4 receptor knockout rescues fertility in ob/ob mice Amanda Sainsbury,1 Christoph Schwarzer,1 Michelle Couzens,1 Arthur Jenkins,3 Samantha R. Oakes,2 Christopher J. Ormandy,2 and Herbert Herzog1,4 1Neurobiology Research Program, 2Cancer Research Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, Darlinghurst, Sydney NSW 2010, Australia; 3Department of Biomedical Sciences, University of Wollongong, Wollongong, NSW 2522, Australia Hypothalamic neuropeptide Y (NPY) has been implicated in the regulation of energy balance and reproduction, and chronically elevated NPY levels in the hypothalamus are associated with obesity and reduced reproductive function. However, it is not known which one of the five cloned Y receptors mediates these effects. Here we show that crossing the Y4 receptor knockout mouse (Y4−/−) onto the ob/ob background restores the reduced plasma testosterone levels of ob/ob mice as well as the reduced testis and seminal vesicle size and morphology to control values. Fertility in the sterile ob/ob mice was greatly improved by Y4 receptor deletion, with 100% of male and 50% of female Y4−/−,ob/ob double knockout mice producing live offspring. Development of the mammary ducts and lobuloalveoli was significantly enhanced in pregnant Y4−/− and Y4−/−,ob/ob females. Consistent with the improved fertility and enhanced mammary gland development, gonadotropin releasing hormone (GnRH) expression was significantly increased in Y4−/− and Y4−/−,ob/ob animals. Y4−/− mice displayed lower body weight and reduced white adipose tissue mass accompanied by increased plasma levels of pancreatic polypeptide (PP).
    [Show full text]
  • And Uterine Glands on Decidualization and Fetoplacental Development
    Sexually dimorphic effects of forkhead box a2 (FOXA2) and uterine glands on decidualization and fetoplacental development Pramod Dhakala, Andrew M. Kellehera, Susanta K. Behuraa,b, and Thomas E. Spencera,c,1 aDivision of Animal Sciences, University of Missouri, Columbia, MO 65211; bInstitute for Data Science and Informatics, University of Missouri, Columbia, MO 65211; and cDepartment of Obstetrics, Gynecology, and Women’s Health, University of Missouri, Columbia, MO 65201 Contributed by Thomas E. Spencer, August 11, 2020 (sent for review July 7, 2020; reviewed by Ramakrishna Kommagani and Geetu Tuteja) Glands of the uterus are essential for pregnancy establishment. the stroma/decidua (15), and recent evidence indicates that Forkhead box A2 (FOXA2) is expressed specifically in the glands of uterine glands influence stromal cell decidualization (15–18). the uterus and a critical regulator of glandular epithelium (GE) Additionally, uterine glands have direct connections to the de- differentiation, development, and function. Mice with a condi- veloping placenta in mice (19, 20) and humans (21). tional deletion of FOXA2 in the adult uterus, created using the Mice lacking leukemia inhibitory factor (LIF) and uterine lactotransferrin iCre (Ltf-iCre) model, have a morphologically gland knockout mice and sheep are infertile, thereby establishing normal uterus with glands, but lack FOXA2-dependent GE- the importance of the uterine glands, their secretions, and expressed genes, such as leukemia inhibitory factor (LIF). Adult products for embryo implantation and pregnancy (22–28). iCre/+ f/f FOXA2 conditional knockout (cKO; Ltf Foxa2 ) mice are infer- Forkhead box (FOX) transcription factors play essential roles in tile due to defective embryo implantation arising from a lack of cell growth, proliferation, and differentiation in a number of LIF, a critical implantation factor of uterine gland origin.
    [Show full text]
  • The Hypothalamo-Prolactin Axis 226:2 T101–T122 Thematic Review
    D R Grattan The hypothalamo-prolactin axis 226:2 T101–T122 Thematic Review Open Access 60 YEARS OF NEUROENDOCRINOLOGY The hypothalamo-prolactin axis David R Grattan1,2 Correspondence should be addressed 1Centre for Neuroendocrinology and Department of Anatomy, University of Otago, to D R Grattan PO Box 913, Dunedin 9054, New Zealand Email 2Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand [email protected] Abstract The hypothalamic control of prolactin secretion is different from other anterior pituitary Key Words hormones, in that it is predominantly inhibitory, by means of dopamine from the tubero- " prolactin infundibular dopamine neurons. In addition, prolactin does not have an endocrine target " tuberoinfundibular tissue, and therefore lacks the classical feedback pathway to regulate its secretion. Instead, dopamine neurons it is regulated by short loop feedback, whereby prolactin itself acts in the brain to stimulate " pregnancy production of dopamine and thereby inhibit its own secretion. Finally, despite its relatively " lactation simplename, prolactin has a broad range offunctions in the body,in addition to its defining role " prolactin-releasing factor in promoting lactation. As such, the hypothalamo-prolactin axis has many characteristics that are quite distinct from other hypothalamo-pituitary systems. This review will provide a brief overview of our current understanding of the neuroendocrine control of prolactin secretion, in particular focusing on the plasticity evident in this system, which keeps prolactin secretion at low levels most of the time, but enables extended periods of hyperprolactinemia when Journal of Endocrinology necessary for lactation. Key prolactin functions beyond milk production will be discussed, particularly focusing on the role of prolactin in inducing adaptive responses in multiple different systems to facilitate lactation, and the consequences if prolactin action is impaired.
    [Show full text]