[en] Prolactin influences a wide range of physiological functions via actions within the central nervous system, as well as in peripheral tissues. A significant limitation in studies investigating these functions is the difficulty in identifying prolactin receptor (Prlr) expression, particularly in the brain. We have developed a novel mouse line using homologous recombination within mouse embryonic stem cells to produce a mouse in which an internal ribosome entry site (IRES) followed by Cre recombinase cDNA is inserted immediately after exon 10 in the Prlr gene, thereby targeting the
long isoform of the Prlr. By crossing this Prlr-IRES-Cre mouse with a ROSA26-CAGStauGFP (τGFP) reporter mouse line, and using immunohistochemistry to detect τGFP, we were able to generate a detailed map of the distribution of individual Prlr expressing neurones and fibres throughout the brain of adult mice without the need for amplification of the GFP signal. Because the τGFP is targeted to neurotubules, the labelling detected not only cell bodies, but also processes of prolactin-sensitive neurones. In both males and females, Cre-dependent τGFP expression was localised, with varying degrees of abundance, in a number of brain regions, including the lateral
septal nucleus, bed nucleus of the stria terminalis, preoptic and hypothalamic nuclei, medial habenula, posterodorsal medial amygdala, and brainstem regions such as the periaqueductal grey and parabrachial nucleus. The labelling was highly specific, occurring only in cells where we could also detect Prlr mRNA by in situ hybridisation.
Apart from two brain areas, the anteroventral periventricular nucleus and the medial preoptic nucleus, the number and distribution of τGFP-immunopositive cells was similar in males and females, suggesting that prolactin may have many equivalent functions in both sexes. These mice provide a valuable tool for investigating the neural circuits underlying the actions of prolactin.
Kokay, Ilona; University of Otago, Dunedin, New Zealand > School of Biomedical Sciences > Centre for Neuroendocrinology and Department of Anatomy
Wyatt, Amanda; Saarland University School of Medicine, Homburg, Germany > Center for Molecular Signaling (PZMS) > Experimental Pharmacology
Phillipps, Hollian; University of Otago, Dunedin, New Zeeland > School of Biomedical Sciences > Centre for Neuroendocrinology and Department of Anatomy
Aoki, Mary; Saarland University School of Medicine, Homburg, Germany > Center for Molecular Signaling (PZMS) > Experimental Pharmacology
Ectors, Fabien ; Université de Liège - ULiège > GIGA Transgenic Platform > Scientifiques attachés au Doyen (FMV)
Boehm, Ulrich; Saarland University School of Medicine, Homburg, Germany > Center for Molecular Signaling (PZMS) > Experimental Pharmacology
Grattan, David; University of Otago, Dunedin, New Zeeland > School of Biomedical Sciences > Centre for Neuroendocrinology and Department of Anatomy
Language :
English
Title :
Analysis of prolactin receptor expression in the murine brain using a novel prolactin receptor reporter mouse
Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA. Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev. 1998;19:225-268
Freeman ME, Kanyicska B, Lerant A, Nagy G. Prolactin: structure, function, and regulation of secretion. Physiol Rev. 2000;80:1523-1631
Grattan DR. 60 years of neuroendocrinology: the hypothalamo-prolactin axis. J Endocrinol. 2015;226:T101-T122
Grattan DR, LeTissier P. Hypothalamic control of prolactin secretion, and the multiple reproductive functions of prolactin. In: Plant TM, Zelesnik AJ, eds. Knobil and Neill's Physiology of Reproduction, 4th edn. Amsterdam: Elsevier; 2015:469-526
Ladyman SR, Augustine RA, Grattan DR. Hormone interactions regulating energy balance during pregnancy. J Neuroendocrinol. 2010;22:805-817
Banerjee RR, Cyphert HA, Walker EM, et al. Gestational diabetes mellitus from inactivation of prolactin receptor and MafB in islet beta-cells. Diabetes. 2016;65:2331-2341
Sorenson RL, Brelje TC. Adaptation of islets of Langerhans to pregnancy: beta-cell growth, enhanced insulin secretion and the role of lactogenic hormones. Horm Metab Res. 1997;29:301-307
Liu X, Brown RS, Herbison AE, Grattan DR. Lactational anovulation in mice results from a selective loss of kisspeptin input to GnRH neurons. Endocrinology. 2014;155:193-203
Bachelot A, Binart N. Reproductive role of prolactin. Reproduction. 2007;133:361-369
Gustafson P, Bunn SJ, Grattan DR. The role of prolactin in the suppression of Crh mRNA expression during pregnancy and lactation in the mouse. J Neuroendocrinol. 2017;29: https://doi.org/10.1111/jne.12511
Bridges RS, Numan M, Ronsheim PM, Mann PE, Lupini CE. Central prolactin infusions stimulate maternal behavior in steroid-treated, nulliparous female rats. Proc Natl Acad Sci USA. 1990;87:8003-8007
Bridges RS, Ronsheim PM. Prolactin (PRL) regulation of maternal behavior in rats: bromocriptine treatment delays and PRL promotes the rapid onset of behavior. Endocrinology. 1990;126:837-848
Sugiyama T, Minoura H, Toyoda N, et al. Pup contact induces the expression of long form prolactin receptor mRNA in the brain of female rats: effects of ovariectomy and hypophysectomy on receptor gene expression. J Endocrinol. 1996;149:335-340
Mann PE, Bridges RS. Lactogenic hormone regulation of maternal behavior. Prog Brain Res. 2001;133:251-262
Brown RSE, Aoki M, Ladyman SR, et al. Prolactin action in the medial preoptic area is necessary for postpartum maternal nursing behavior. Proc Natl Acad Sci USA. 2017;114:10779-10784
Clemens JA, Meites J. Inhibition by hypothalamic prolactin implants of prolactin secretion, mammary growth and luteal function. Endocrinology. 1968;82:878-881
Ben-Jonathan N. Dopamine: a prolactin-inhibiting hormone. Endocr Rev. 1985;6:564-589
Lyons DJ, Hellysaz A, Broberger C. Prolactin regulates tuberoinfundibular dopamine neuron discharge pattern: novel feedback control mechanisms in the lactotrophic axis. J Neurosci. 2012;32:8074-8083
Romano N, Yip SH, Hodson DJ, et al. Plasticity of hypothalamic dopamine neurons during lactation results in dissociation of electrical activity and release. J Neurosci. 2013;33:4424-4433
Torner L. Actions of prolactin in the brain: from physiological adaptations to stress and neurogenesis to psychopathology. Front Endocrinol (Lausanne). 2016;7:25
Donato J Jr, Frazao R. Interactions between prolactin and kisspeptin to control reproduction. Arch Endocrinol Metab. 2016;60:587-595
Bales KL, Saltzman W. Fathering in rodents: neurobiological substrates and consequences for offspring. Horm Behav. 2016;77:249-259
Saltzman W, Ziegler TE. Functional significance of hormonal changes in mammalian fathers. J Neuroendocrinol. 2014;26:685-696
Mak GK, Weiss S. Paternal recognition of adult offspring mediated by newly generated CNS neurons. Nat Neurosci. 2010;13:753-758
Fleming AS, Corter C, Stallings J, Steiner M. Testosterone and prolactin are associated with emotional responses to infant cries in new fathers. Horm Behav. 2002;42:399-413
Storey AE, Walsh CJ, Quinton RL, Wynne-Edwards KE. Hormonal correlates of paternal responsiveness in new and expectant fathers. Evol Hum Behav. 2000;21:79-95
Gettler LT, McDade TW, Feranil AB, Kuzawa CW. Prolactin, fatherhood, and reproductive behavior in human males. Am J Phys Anthropol. 2012;148:362-370
Chiu S, Wise PM. Prolactin receptor mRNA localization in the hypothalamus by in situ hybridization. J Neuroendocrinol. 1994;6:191-199
Bakowska JC, Morrell JI. Atlas of the neurons that express mRNA for the long form of the prolactin receptor in the forebrain of the female rat. J Comp Neurol. 1997;386:161-177
Brown RS, Kokay IC, Herbison AE, Grattan DR. Distribution of prolactin-responsive neurons in the mouse forebrain. J Comp Neurol. 2010;518:92-102
Arbogast LA, Voogt JL. Prolactin (PRL) receptors are colocalized in dopaminergic neurons in fetal hypothalamic cell cultures: effect of PRL on tyrosine hydroxylase activity. Endocrinology. 1997;138:3016-3023
Lerant A, Freeman ME. Ovarian steroids differentially regulate the expression of prolactin receptors in neuroendocrine dopaminergic neuron populations – a double-label confocal microscopic study. Brain Res. 1998;802:141-154
Pi XJ, Grattan DR. Distribution of prolactin receptor immunoreactivity in the brain of estrogen-treated, ovariectomized rats. J Comp Neurol. 1998;394:462-474
Pi XJ, Grattan DR. Increased prolactin receptor immunoreactivity in the hypothalamus of lactating rats. J Neuroendocrinol. 1999;11:693-705
Roky R, Paut-Pagano L, Goffin V, et al. Distribution of prolactin receptors in the rat forebrain. Immunohistochemical study. Neuroendocrinology. 1996;63:422-429
Furigo IC, Metzger M, Teixeira PD, Soares CR, Donato J Jr. Distribution of growth hormone-responsive cells in the mouse brain. Brain Struct Funct. 2017;222:341-363
Salais-Lopez H, Lanuza E, Agustin-Pavon C, Martinez-Garcia F. Tuning the brain for motherhood: prolactin-like central signalling in virgin, pregnant, and lactating female mice. Brain Struct Funct. 2017;222:895-921
Candlish M, De Angelis R, Gotz V, Boehm U. Gene targeting in neuroendocrinology. Compr Physiol. 2015;5:1645-1676
LaPensee CR, Horseman ND, Tso P, Brandebourg TD, Hugo ER, Ben-Jonathan N. The prolactin-deficient mouse has an unaltered metabolic phenotype. Endocrinology. 2006;147:4638-4645
Amenomori Y, Chen CL, Meites J. Serum prolactin levels in rats during different reproductive states. Endocrinology. 1970;86:506-510
Nagy A, Gertsenstein M, Vinterstein K, Behringer R. Manipulating the Mouse Embryo: A Laboratory Manual. 3rd Edition, New York: Cold Spring Harbor Laboratory Press, 2003
Rodriguez CI, Buchholz F, Galloway J, et al. High-efficiency deleter mice show that FLPe is an alternative to Cre-loxP. Nat Genet. 2000;25:139-140
Wen S, Gotze IN, Mai O, Schauer C, Leinders-Zufall T, Boehm U. Genetic identification of GnRH receptor neurons: a new model for studying neural circuits underlying reproductive physiology in the mouse brain. Endocrinology. 2011;152:1515-1526
Paxinos G, Franklin KBJ. The Mouse Brain in Stereotaxic Coordinates. San Diego, CA: Elsevier Academic Press; 2008
Tejadilla D, Cerbon M, Morales T. Prolactin reduces the damaging effects of excitotoxicity in the dorsal hippocampus of the female rat independently of ovarian hormones. Neuroscience. 2010;169:1178-1185
Vergara-Castaneda E, Grattan DR, Pasantes-Morales H, et al. Prolactin mediates neuroprotection against excitotoxicity in primary cell cultures of hippocampal neurons via its receptor. Brain Res. 2016;1636:193-199
Grattan DR. The actions of prolactin in the brain during pregnancy and lactation. Prog Brain Res. 2001;133:153-171
Kokay IC, Grattan DR. Expression of mRNA for prolactin receptor (long form) in dopamine and pro-opiomelanocortin neurones in the arcuate nucleus of non-pregnant and lactating rats. J Neuroendocrinol. 2005;17:827-835
Brown RS, Kokay IC, Phillipps HR, et al. Conditional deletion of the prolactin receptor reveals functional subpopulations of dopamine neurons in the arcuate nucleus of the hypothalamus. J Neurosci. 2016;36:9173-9185
Kokay IC, Bull PM, Davis RL, Ludwig M, Grattan DR. Expression of the long form of the prolactin receptor in magnocellular oxytocin neurons is associated with specific prolactin regulation of oxytocin neurons. Am J Physiol Regul Integr Comp Physiol. 2006;290:R1216-R1225
Townsend J, Cave BJ, Norman MR, et al. Effects of prolactin on hypothalamic supraoptic neurones: evidence for modulation of STAT5 expression and electrical activity. Neuro Endocrinol Lett. 2005;26:125-130
Sapsford TJ, Kokay IC, Ostberg L, Bridges RS, Grattan DR. Differential sensitivity of specific neuronal populations of the rat hypothalamus to prolactin action. J Comp Neurol. 2012;520:1062-1077
Ben-Jonathan N, Hnasko R. Dopamine as a prolactin (PRL) inhibitor. Endocr Rev. 2001;22:724-763
Clarke DL, Arey BJ, Linzer DI. Prolactin receptor messenger ribonucleic acid expression in the ovary during the rat estrous cycle. Endocrinology. 1993;133:2594-2603
Tabata H, Kobayashi M, Ikeda JH, Nakao N, Saito TR, Tanaka M. Characterization of multiple first exons in murine prolactin receptor gene and the effect of prolactin on their expression in the choroid plexus. J Mol Endocrinol. 2012;48:169-176
Cave BJ, Norman M, Flynn A, Townsend J, Wakerley JB, Tortonese DJ. Prolactin-induced activation of STAT5 within the hypothalamic arcuate nucleus. NeuroReport. 2005;16:1423-1426
Brown RS, Wyatt AK, Herbison RE, et al. Prolactin transport into mouse brain is independent of prolactin receptor. FASEB J. 2016;30:1002-1010
Leshan RL, Louis GW, Jo YH, Rhodes CJ, Munzberg H, Myers MG Jr. Direct innervation of GnRH neurons by metabolic- and sexual odorant-sensing leptin receptor neurons in the hypothalamic ventral premammillary nucleus. J Neurosci. 2009;29:3138-3147
Simerly RB. Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain. Annu Rev Neurosci. 2002;25:507-536
Brown RS, Herbison AE, Grattan DR. Prolactin regulation of kisspeptin neurones in the mouse brain and its role in the lactation-induced suppression of kisspeptin expression. J Neuroendocrinol. 2014;26:898-908
Clarkson J, Herbison AE. Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology. 2006;147:5817-5825
Numan M. A neural circuitry analysis of maternal behavior in the rat. Acta Paediatr Suppl. 1994;397:19-28
Kohl J, Autry AE, Dulac C. The neurobiology of parenting: a neural circuit perspective. BioEssays. 2017;39:1-11
Grattan DR, Bridges RS. Prolactin actions in the brain. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT, eds. Hormones, Brain and Behavior, 2nd edn. San Diego, CA: Academic Press; 2009:2471-2503
Korf HW. Signaling pathways to and from the hypophysial pars tuberalis, an important center for the control of seasonal rhythms. Gen Comp Endocrinol. 2018;258:236-243
