{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:21:03Z","timestamp":1791264063865,"version":"4.1.0"},"reference-count":42,"publisher":"The Endocrine Society","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>GnRH is a key player in the hypothalamic control of gonadotropin secretion from the anterior pituitary gland. It has been shown that the mammalian counterpart of the avian gonadotropin inhibitory hormone named RFamide-related peptide (RFRP) is expressed in hypothalamic neurons that innervate and inhibit GnRH neurons. The RFRP precursor is processed into 2 mature peptides, RFRP-1 and RFRP-3. These are characterized by a conserved C-terminal motif RF-NH2 but display highly different N termini. Even though the 2 peptides are equally potent in vitro, little is known about their relative distribution and their distinct roles in vivo. In this study, we raised an antiserum selective for RFRP-1 and defined the distribution of RFRP-1-immunoreactive (ir) neurons in the rat brain. Next, we analyzed the level of RFRP-1-ir during postnatal development in males and females and investigated changes in RFRP-1-ir during the estrous cycle. RFRP-1-ir neurons were distributed along the third ventricle from the caudal part of the medial anterior hypothalamus throughout the medial tuberal hypothalamus and were localized in, but mostly in between, the dorsomedial hypothalamic, ventromedial hypothalamic, and arcuate nuclei. The number of RFRP-1-ir neurons and the density of cellular immunoreactivity were unchanged from juvenile to adulthood in male rats during the postnatal development. However, both parameters were significantly increased in female rats from peripuberty to adulthood, demonstrating prominent gender difference in the developmental control of RFRP-1 expression. The percentage of c-Fos-positive RFRP-1-ir neurons was significantly higher in diestrus as compared with proestrus and estrus. In conclusion, we found that adult females, as compared with males, have significantly more RFRP-1-ir per cell, and these cells are regulated during the estrous cycle.<\/jats:p>","DOI":"10.1210\/en.2014-1274","type":"journal-article","created":{"date-parts":[[2014,8,21]],"date-time":"2014-08-21T17:20:59Z","timestamp":1408641659000},"page":"4402-4410","source":"Crossref","is-referenced-by-count":23,"title":["Changes in RFamide-Related Peptide-1 (RFRP-1)-Immunoreactivity During Postnatal Development and the Estrous Cycle"],"prefix":"10.1210","volume":"155","author":[{"given":"Sara R.","family":"J\u00f8rgensen","sequence":"first","affiliation":[{"name":"Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, DK-2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mille D.","family":"Andersen","sequence":"first","affiliation":[{"name":"Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, DK-2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnete","family":"Overgaard","sequence":"first","affiliation":[{"name":"Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, DK-2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens D.","family":"Mikkelsen","sequence":"first","affiliation":[{"name":"Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, DK-2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","reference":[{"key":"2020071611543447800_B1","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1111\/j.1365-2826.2008.01784.x","article-title":"RFamide-related peptide and its cognate receptor in the sheep: cDNA cloning, mRNA distribution in the hypothalamus and the effect of photoperiod","volume":"20","author":"Dardente","year":"2008","journal-title":"J Neuroendocrinol"},{"key":"2020071611543447800_B2","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/S0167-4889(01)00135-5","article-title":"Characteristics and distribution of endogenous RFamide-related peptide-1","volume":"1540","author":"Fukusumi","year":"2001","journal-title":"Biochim Biophys Acta"},{"key":"2020071611543447800_B3","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/35036326","article-title":"New neuropeptides containing carboxy-terminal RFamide and their receptor in mammals","volume":"2","author":"Hinuma","year":"2000","journal-title":"Nat Cell Biol"},{"key":"2020071611543447800_B4","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1093\/icb\/icn019","article-title":"The control of reproductive physiology and behavior by gonadotropin-inhibitory hormone","volume":"48","author":"Ubuka","year":"2008","journal-title":"Integ Comp Biol"},{"key":"2020071611543447800_B5","doi-asserted-by":"crossref","first-page":"e8400","DOI":"10.1371\/journal.pone.0008400","article-title":"Identification of human GnIH homologs, RFRP-1 and RFRP-3, and the cognate receptor, GPR147 in the human hypothalamic pituitary axis","volume":"4","author":"Ubuka","year":"2009","journal-title":"PLoS One"},{"key":"2020071611543447800_B6","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0014-5793(02)02275-5","article-title":"A novel rat hypothalamic RFamide-related peptide identified by immunoaffinity chromatography and mass spectrometry","volume":"512","author":"Ukena","year":"2002","journal-title":"FEBS Lett"},{"key":"2020071611543447800_B7","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1002\/cne.22191","article-title":"Gonadotropin-inhibitory hormone identification, cDNA cloning, and distribution in rhesus macaque brain","volume":"517","author":"Ubuka","year":"2009","journal-title":"J Comp Neurol"},{"key":"2020071611543447800_B8","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1677\/JOE-08-0197","article-title":"Hypophysiotropic role of RFamide-related peptide-3 in the inhibition of LH secretion in female rats","volume":"199","author":"Murakami","year":"2008","journal-title":"J Endocrinol"},{"key":"2020071611543447800_B9","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1210\/en.2011-1110","article-title":"Identification, expression, and physiological functions of Siberian hamster gonadotropin-inhibitory hormone","volume":"153","author":"Ubuka","year":"2012","journal-title":"Endocrinology"},{"key":"2020071611543447800_B10","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.yhbeh.2006.09.009","article-title":"Rat RFamide-related peptide-3 stimulates GH secretion, inhibits LH secretion, and has variable effects on sex behavior in the adult male rat","volume":"51","author":"Johnson","year":"2007","journal-title":"Horm Behav"},{"key":"2020071611543447800_B11","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1111\/j.1365-2826.2010.02031.x","article-title":"The roles of RFamide-related peptide-3 in mammalian reproductive function and behaviour","volume":"22","author":"Kriegsfeld","year":"2010","journal-title":"J Neuroendocrinol"},{"key":"2020071611543447800_B12","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.1073\/pnas.0511003103","article-title":"Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals","volume":"103","author":"Kriegsfeld","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071611543447800_B13","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1159\/000145718","article-title":"Rat RFRP-3 alters hypothalamic GHRH expression and growth hormone secretion but does not affect KiSS-1 gene expression or the onset of puberty in male rats","volume":"88","author":"Johnson","year":"2008","journal-title":"Neuroendocrinology"},{"key":"2020071611543447800_B14","doi-asserted-by":"crossref","first-page":"2799","DOI":"10.1210\/en.2008-1623","article-title":"RFamide-related peptide-3, a mammalian gonadotropin-inhibitory hormone ortholog, regulates gonadotropin-releasing hormone neuron firing in the mouse","volume":"150","author":"Ducret","year":"2009","journal-title":"Endocrinology"},{"key":"2020071611543447800_B15","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1113\/jphysiol.2008.166447","article-title":"Gonadotropin inhibitory hormone inhibits basal forebrain vGluT2-gonadotropin-releasing hormone neurons via a direct postsynaptic mechanism","volume":"587","author":"Wu","year":"2009","journal-title":"J Physiol"},{"key":"2020071611543447800_B16","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1210\/en.2011-1622","article-title":"Stimulatory effect of RFRP-3 on the gonadotrophic axis in the male Syrian hamster: the exception proves the rule","volume":"153","author":"Ancel","year":"2012","journal-title":"Endocrinology"},{"key":"2020071611543447800_B17","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1385\/ENDO:20:1-2:59","article-title":"Prolactin-releasing peptide and its homolog RFRP-1 act in hypothalamus but not in anterior pituitary gland to stimulate stress hormone secretion","volume":"20","author":"Samson","year":"2003","journal-title":"Endocrine"},{"key":"2020071611543447800_B18","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/S0006-8993(03)02877-4","article-title":"Localization and neuronal response of RFamide related peptides in the rat central nervous system","volume":"982","author":"Yano","year":"2003","journal-title":"Brain Res"},{"key":"2020071611543447800_B19","doi-asserted-by":"crossref","first-page":"876","DOI":"10.1111\/jne.12084","article-title":"Kisspeptin neurones do not directly signal to RFRP-3 neurones but RFRP-3 may directly modulate a subset of hypothalamic kisspeptin cells in mice","volume":"25","author":"Poling","year":"2013","journal-title":"J Neuroendocrinol"},{"key":"2020071611543447800_B20","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/S0304-3940(01)01583-X","article-title":"Distribution of novel RFamide-related peptide-like immunoreactivity in the mouse central nervous system","volume":"300","author":"Ukena","year":"2001","journal-title":"Neurosci Lett"},{"key":"2020071611543447800_B21","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1210\/en.2011-2049","article-title":"Development, sex steroid regulation, and phenotypic characterization of RFamide-related peptide (Rfrp) gene expression and RFamide receptors in the mouse hypothalamus","volume":"153","author":"Poling","year":"2012","journal-title":"Endocrinology"},{"key":"2020071611543447800_B22","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.ijdevneu.2011.10.003","article-title":"Developmental changes in the mammalian gonadotropin-inhibitory hormone (GnIH) ortholog RFamide-related peptide (RFRP) and its cognate receptor GPR147 in the rat hypothalamus","volume":"30","author":"Iwasa","year":"2012","journal-title":"Int J Dev Neurosci"},{"key":"2020071611543447800_B23","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1111\/j.1365-2826.2010.01963.x","article-title":"Developmental and steroidogenic effects on the gene expression of RFamide related peptides and their receptor in the rat brain and pituitary gland","volume":"22","author":"Quennell","year":"2010","journal-title":"J Neuroendocrinol"},{"key":"2020071611543447800_B24","doi-asserted-by":"crossref","first-page":"168","DOI":"10.3389\/fendo.2012.00168","article-title":"RFRP neurons are critical gatekeepers for the photoperiodic control of reproduction","volume":"3","author":"Simonneaux","year":"2012","journal-title":"Front Endocrinol (Lausanne)"},{"key":"2020071611543447800_B25","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1095\/biolreprod.110.085407","article-title":"Hypothalamic expression of KISS1 and gonadotropin inhibitory hormone genes during the menstrual cycle of a non-human primate","volume":"83","author":"Smith","year":"2010","journal-title":"Biol Reprod"},{"key":"2020071611543447800_B26","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.yfrne.2010.03.001","article-title":"Gonadotropin-inhibitory hormone (GnIH) and its control of central and peripheral reproductive function","volume":"31","author":"Tsutsui","year":"2010","journal-title":"Front Neuroendocrinol"},{"key":"2020071611543447800_B27","doi-asserted-by":"crossref","first-page":"4958","DOI":"10.1210\/en.2008-0316","article-title":"Alterations in RFamide-related peptide expression are coordinated with the preovulatory luteinizing hormone surge","volume":"149","author":"Gibson","year":"2008","journal-title":"Endocrinology"},{"key":"2020071611543447800_B28","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1210\/en.2010-1418","article-title":"Estradiol down-regulates RF-amide-related peptide (RFRP) expression in the mouse hypothalamus","volume":"152","author":"Moln\u00e1r","year":"2011","journal-title":"Endocrinology"},{"key":"2020071611543447800_B29","doi-asserted-by":"crossref","first-page":"3368","DOI":"10.1210\/en.2012-1088","article-title":"Gonadotropin-inhibitory hormone (GnIH) secretion into the ovine hypophyseal portal system","volume":"153","author":"Smith","year":"2012","journal-title":"Endocrinology"},{"key":"2020071611543447800_B30","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1002\/bdrb.20106","article-title":"The rodent estrous cycle: characterization of vaginal cytology and its utility in toxicological studies","volume":"80","author":"Goldman","year":"2007","journal-title":"Birth Defects Res B Dev Reprod Toxicol"},{"key":"2020071611543447800_B31","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1113\/jphysiol.2004.072298","article-title":"Advanced vaginal opening and precocious activation of the reproductive axis by KiSS-1 peptide, the endogenous ligand of GPR54","volume":"561","author":"Navarro","year":"2004","journal-title":"J Physiol"},{"key":"2020071611543447800_B32","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1095\/biolreprod17.2.298","article-title":"Preputial separation as an external sign of pubertal development in the male rat","volume":"17","author":"Korenbrot","year":"1977","journal-title":"Biol Reproduct"},{"key":"2020071611543447800_B33","first-page":"83","article-title":"An immunohistochemical demonstration of gastrin-releasing peptide (GRP) in the rat substantia nigra","volume":"2","author":"Larsen","year":"1989","journal-title":"J Chem Neuroanat"},{"key":"2020071611543447800_B34","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1111\/j.1365-2826.2009.01886.x","article-title":"Projections of RFamide-related peptide-3 neurones in the ovine hypothalamus, with special reference to regions regulating energy balance and reproduction","volume":"21","author":"Qi","year":"2009","journal-title":"J Neuroendocrinol"},{"key":"2020071611543447800_B35","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1210\/en.2008-1287","article-title":"Cells expressing RFamide-related peptide-1\/3, the mammalian gonadotropin-inhibitory hormone orthologs, are not hypophysiotropic neuroendocrine neurons in the rat","volume":"150","author":"Rizwan","year":"2009","journal-title":"Endocrinology"},{"key":"2020071611543447800_B36","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/S0361-9230(98)00121-X","article-title":"Expression of Fos in the circadian system following nonphotic stimulation","volume":"47","author":"Mikkelsen","year":"1998","journal-title":"Brain Res Bull"},{"key":"2020071611543447800_B37","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1002\/cne.10858","article-title":"Magic peptides, magic antibodies: guidelines for appropriate controls for immunohistochemistry","volume":"465","author":"Saper","year":"2003","journal-title":"J Comp Neurol"},{"key":"2020071611543447800_B38","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1111\/j.1471-4159.1989.tb07407.x","article-title":"Characterization and regional distribution of peptides derived from the vasoactive intestinal peptide precursor in the normal human brain","volume":"53","author":"Fahrenkrug","year":"1989","journal-title":"J Neurochem"},{"key":"2020071611543447800_B39","doi-asserted-by":"crossref","first-page":"1409","DOI":"10.1152\/physrev.00034.2006","article-title":"The physiology of glucagon-like peptide 1","volume":"87","author":"Holst","year":"2007","journal-title":"Physiol Rev"},{"key":"2020071611543447800_B40","doi-asserted-by":"crossref","first-page":"4201","DOI":"10.1210\/en.2006-1686","article-title":"Neuropeptide processing and its impact on melanocortin pathways","volume":"148","author":"Pritchard","year":"2007","journal-title":"Endocrinology"},{"key":"2020071611543447800_B41","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1210\/en.2007-0848","article-title":"RFamide-related peptide gene is a melatonin-driven photoperiodic gene","volume":"149","author":"Revel","year":"2008","journal-title":"Endocrinology"},{"key":"2020071611543447800_B42","doi-asserted-by":"crossref","first-page":"5770","DOI":"10.1210\/en.2008-0581","article-title":"Variation in kisspeptin and RFamide-related peptide (RFRP) expression and terminal connections to gonadotropin-releasing hormone neurons in the brain: a novel medium for seasonal breeding in the sheep","volume":"149","author":"Smith","year":"2008","journal-title":"Endocrinology"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/155\/11\/4402\/10828190\/endo4402.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/155\/11\/4402\/10828190\/endo4402.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T17:55:46Z","timestamp":1594922146000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/155\/11\/4402\/2422670"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2014,11,1]]},"references-count":42,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2014,11,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2014-1274","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,11,1]]}}}