{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:00:22Z","timestamp":1792677622401,"version":"4.5.0"},"reference-count":58,"publisher":"The Endocrine Society","issue":"11","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2015,11,1]]},"abstract":"<jats:p>The function and components of the hypothalamic-pituitary axis are conserved among vertebrates; however, in fish, a neuroglandular mode of delivery (direct contact between axons and endocrine cells) was considered dominant, whereas in tetrapods hypothalamic signals are relayed to their targets via the hypophysial portal blood system (neurovascular delivery mode). By using a transgenic zebrafish model we studied the functional and anatomical aspects of gonadotrope regulation thus revisiting the existing model. FSH cells were found to be situated close to the vasculature whereas the compact organization of LH cells prevented direct contact of all cells with the circulation. GnRH3 fibers formed multiple boutons upon reaching the pituitary, but most of these structures were located in the neurohypophysis rather than adjacent to gonadotropes. A close association was observed between FSH cells and GnRH3 boutons, but only a fifth of the LH cells were in direct contact with GnRH3 axons, suggesting that FSH cells are more directly regulated than LH cells. GnRH3 fibers closely followed the vasculature in the neurohypophysis and formed numerous boutons along these tracts. These vessels were found to be permeable to relatively large molecules, suggesting the uptake of GnRH3 peptides. Our findings have important implications regarding the differential regulation of LH and FSH and contradict the accepted notion that fish pituitary cells are mostly regulated directly by hypothalamic fibers. Instead, we provide evidence that zebrafish apply a dual mode of gonadotrope regulation by GnRH3 that combines both neuroglandular and neurovascular components.<\/jats:p>","DOI":"10.1210\/en.2015-1150","type":"journal-article","created":{"date-parts":[[2015,8,11]],"date-time":"2015-08-11T17:00:56Z","timestamp":1439312456000},"page":"4163-4173","source":"Crossref","is-referenced-by-count":72,"title":["Architecture of GnRH-Gonadotrope-Vasculature Reveals a Dual Mode of Gonadotropin Regulation in Fish"],"prefix":"10.1210","volume":"156","author":[{"given":"Matan","family":"Golan","sequence":"first","affiliation":[{"name":"Department of Animal Sciences (M.G., B.L.-S.), The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Einat","family":"Zelinger","sequence":"first","affiliation":[{"name":"The Interdepartmental Equipment Unit (E.Z.), The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonathan","family":"Zohar","sequence":"first","affiliation":[{"name":"Department of Marine Biotechnology (Y.Z.), University of Maryland Baltimore County and Institute of Marine and Environmental Technology, Baltimore, Maryland 21202"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berta","family":"Levavi-Sivan","sequence":"first","affiliation":[{"name":"Department of Animal Sciences (M.G., B.L.-S.), The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2015,8,11]]},"reference":[{"issue":"3","key":"2020071611592304900_B1","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1677\/jme.1.01600","article-title":"Regulation of gonadotropin subunit gene transcription","volume":"33","author":"Burger","year":"2004","journal-title":"J Mol Endocrinol"},{"key":"2020071611592304900_B2","first-page":"25","article-title":"Hypophyseal-gonadal relationships in the male","volume-title":"Principles of Medical Biology","author":"Hedger","year":"1998"},{"key":"2020071611592304900_B3","first-page":"57","article-title":"Hypophyseal-ovarian relationships","volume-title":"Principles of Medical Biology","author":"Mroueh","year":"1998"},{"issue":"4","key":"2020071611592304900_B4","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1093\/humupd\/dmu009","article-title":"The kisspeptin-GnRH pathway in human reproductive health and disease","volume":"20","author":"Skorupskaite","year":"2014","journal-title":"Hum Reprod Update"},{"issue":"3","key":"2020071611592304900_B5","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"},{"issue":"3","key":"2020071611592304900_B6","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1038\/ng.306","article-title":"TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction","volume":"41","author":"Topaloglu","year":"2009","journal-title":"Nat Genet"},{"key":"2020071611592304900_B7","doi-asserted-by":"crossref","first-page":"3676","DOI":"10.1038\/srep03676","article-title":"Comprehensive analysis of GnRH2 neuronal projections in zebrafish","volume":"4","author":"Xia","year":"2014","journal-title":"Sci Rep"},{"issue":"4","key":"2020071611592304900_B8","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1097\/MED.0b013e32832d88fb","article-title":"The biology of gonadotroph regulation","volume":"16","author":"Ciccone","year":"2009","journal-title":"Curr Opin Endocrinol Diabetes Obes"},{"issue":"2","key":"2020071611592304900_B9","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1677\/jme.0.0320467","article-title":"Differential secretion of gonadotrophins: investigation of the role of secretogranin the release of LH and FSHII and chromogranin A in in L\u03b2T2 cells","volume":"32","author":"Nicol","year":"2004","journal-title":"J Mol Endocrinol"},{"issue":"8","key":"2020071611592304900_B10","doi-asserted-by":"crossref","first-page":"2465","DOI":"10.1016\/j.fertnstert.2010.03.034","article-title":"Mechanisms of FSH synthesis: what we know, what we don\u2019t, and why you should care","volume":"93","author":"Bernard","year":"2010","journal-title":"Fertil Steril"},{"issue":"5","key":"2020071611592304900_B11","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/nrg2091","article-title":"Animal models of human disease: zebrafish swim into view","volume":"8","author":"Lieschke","year":"2007","journal-title":"Nat Rev Genet"},{"key":"2020071611592304900_B12","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1146\/annurev-physiol-012110-142320","article-title":"Zebrafish in endocrine systems: recent advances and implications for human disease","volume":"73","author":"L\u00f6hr","year":"2011","journal-title":"Annu Rev Physiol"},{"key":"2020071611592304900_B13","article-title":"The Pituitary Gland - A Comparative Account","author":"Holmes","year":"1974"},{"issue":"3","key":"2020071611592304900_B14","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1016\/j.ygcen.2009.07.019","article-title":"Perspectives on fish gonadotropins and their receptors","volume":"165","author":"Levavi-Sivan","year":"2010","journal-title":"Gen Comp Endocrinol"},{"issue":"3","key":"2020071611592304900_B15","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.ygcen.2009.04.017","article-title":"Neuroendocrinology of reproduction in teleost fish","volume":"165","author":"Zohar","year":"2010","journal-title":"Gen Comp Endocrinol"},{"key":"2020071611592304900_B16","doi-asserted-by":"crossref","first-page":"182","DOI":"10.3389\/fendo.2014.00182","article-title":"A novel model for development, organization, and function of gonadotropes in fish pituitary","volume":"5","author":"Golan","year":"2014","journal-title":"Front Endocrinol. (Lausanne)"},{"issue":"18","key":"2020071611592304900_B17","doi-asserted-by":"crossref","first-page":"4193","DOI":"10.1242\/dev.01970","article-title":"Genetic and cellular analyses of zebrafish atrioventricular cushion and valve development","volume":"132","author":"Beis","year":"2005","journal-title":"Development"},{"issue":"6","key":"2020071611592304900_B18","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1101\/gad.1629408","article-title":"Foxn4 directly regulates tbx2b expression and atrioventricular canal formation","volume":"22","author":"Chi","year":"2008","journal-title":"Genes Dev"},{"issue":"3","key":"2020071611592304900_B19","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1111\/j.1365-2826.2008.01654.x","article-title":"Early development of forebrain gonadotrophin-releasing hormone (GnRH) neurones and the role of GnRH as an autocrine migration factor","volume":"20","author":"Abraham","year":"2008","journal-title":"J Neuroendocr"},{"issue":"1","key":"2020071611592304900_B20","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/j.ygcen.2012.04.002","article-title":"Steroidogenic response of carp ovaries to piscine FSH and LH depends on the reproductive phase","volume":"178","author":"Aizen","year":"2012","journal-title":"Gen Comp Endocrinol"},{"issue":"26","key":"2020071611592304900_B21","doi-asserted-by":"crossref","first-page":"10269","DOI":"10.1073\/pnas.1119165109","article-title":"Neurokinin Bs and neurokinin B receptors in zebrafish-potential role in controlling fish reproduction","volume":"109","author":"Biran","year":"2012","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071611592304900_B22","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.ygcen.2013.04.032","article-title":"Social dominance in tilapia is associated with gonadotroph hyperplasia","volume":"192","author":"Golan","year":"2013","journal-title":"Gen Comp Endocrinol"},{"issue":"34","key":"2020071611592304900_B23","first-page":"1645","article-title":"Retro-orbital injection in adult zebrafish","volume":"pii","author":"Pugach","year":"2009","journal-title":"J Vis Exp"},{"issue":"3","key":"2020071611592304900_B24","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1007\/BF00212547","article-title":"Ultrastructural characterization of neurosecretory fibres immunoreactive for vasotocin, isotocin, somatostatin, LHRH and CRF in the pituitary of a teleost fish, Poecilia latipinna","volume":"244","author":"Batten","year":"1986","journal-title":"Cell Tissue Res"},{"issue":"3","key":"2020071611592304900_B25","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1007\/BF00220300","article-title":"Ultrastructure of the neurohypophysis of the teleost Poecilia latipinna in relation to neural control of the adenohypophysial cells","volume":"185","author":"Batten","year":"1977","journal-title":"Cell Tissue Res"},{"issue":"2","key":"2020071611592304900_B26","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/BF00312837","article-title":"Origin of the pituitary innervation in the goldfish","volume":"273","author":"Anglade","year":"1993","journal-title":"Cell Tissue Res"},{"issue":"7","key":"2020071611592304900_B27","doi-asserted-by":"crossref","first-page":"3394","DOI":"10.1210\/en.2011-2022","article-title":"Time-of-day-dependent changes in GnRH1 neuronal activities and gonadotropin mRNA expression in a daily spawning fish, medaka","volume":"153","author":"Karigo","year":"2012","journal-title":"Endocrinology"},{"issue":"11","key":"2020071611592304900_B28","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1111\/j.1365-2826.2012.02350.x","article-title":"Interaction between dopamine- and isotocin-containing neurones in the preoptic area of the catfish, Clarias batrachus: role in the regulation of luteinising hormone cells","volume":"24","author":"Singh","year":"2012","journal-title":"J Neuroendocr"},{"issue":"30","key":"2020071611592304900_B29","doi-asserted-by":"crossref","first-page":"12515","DOI":"10.1073\/pnas.1105929108","article-title":"Related pituitary cell lineages develop into interdigitated 3D cell networks","volume":"108","author":"Budry","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"issue":"10","key":"2020071611592304900_B30","doi-asserted-by":"crossref","first-page":"4729","DOI":"10.1210\/en.2012-1360","article-title":"Gonadotrope plasticity at cellular and population levels","volume":"153","author":"Alim","year":"2012","journal-title":"Endocrinology"},{"issue":"1\u20132","key":"2020071611592304900_B31","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.mce.2013.03.022","article-title":"Signal transduction involved in GnRH2-stimulation of identified LH-producing gonadotropes from lhb-GFP transgenic medaka (Oryzias latipes)","volume":"372","author":"Strandab\u00f8","year":"2013","journal-title":"Mol Cell Endocrinol"},{"issue":"3","key":"2020071611592304900_B32","first-page":"1","article-title":"Ontogenic expression profiles of gonadotropins (fshb and lhb) and growth hormone (gh) during sexual differentiation and puberty onset in female zebrafish","volume":"86","author":"Chen","year":"2011","journal-title":"Biol Reprod"},{"key":"2020071611592304900_B33","article-title":"Hormones and Their Receptors in Fish Reproduction","author":"Chong","year":"2005"},{"issue":"37","key":"2020071611592304900_B34","doi-asserted-by":"crossref","first-page":"16372","DOI":"10.1073\/pnas.1000423107","article-title":"Embryonic gonadotropin-releasing hormone signaling is necessary for maturation of the male reproductive axis","volume":"107","author":"Wen","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"issue":"10","key":"2020071611592304900_B35","doi-asserted-by":"crossref","first-page":"2540","DOI":"10.1096\/fj.06-7342com","article-title":"Exocytosis of norepinephrine at axon varicosities and neuronal cell bodies in the rat brain","volume":"21","author":"Chiti","year":"2007","journal-title":"FASEB J"},{"issue":"4","key":"2020071611592304900_B36","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.neuint.2003.11.016","article-title":"Nonsynaptic communication in the central nervous system","volume":"45","author":"Vizi","year":"2004","journal-title":"Neurochem Int"},{"issue":"6","key":"2020071611592304900_B37","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1210\/en.2008-1636","article-title":"Large neurohypophysial varicosities amplify action potentials: results from numerical simulations","volume":"150","author":"Bennett","year":"2009","journal-title":"Endocrinology"},{"issue":"7","key":"2020071611592304900_B38","doi-asserted-by":"crossref","first-page":"e22543","DOI":"10.1371\/journal.pone.0022543","article-title":"Axonal varicosity density as an index of local neuronal interactions","volume":"6","author":"Zhang","year":"2011","journal-title":"PLoS One"},{"issue":"6","key":"2020071611592304900_B39","doi-asserted-by":"crossref","first-page":"732","DOI":"10.1111\/j.1365-2826.2008.01712.x","article-title":"Glial-gonadotrophin hormone (GnRH) neurone interactions in the median eminence and the control of GnRH secretion","volume":"20","author":"Ojeda","year":"2008","journal-title":"J Neuroendocrinol"},{"issue":"4","key":"2020071611592304900_B40","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1007\/s10735-011-9335-5","article-title":"Histological characterization of gonadotropin-releasing hormone (GnRH) in the hypothalamus of the South American plains vizcacha (Lagostomus maximus)","volume":"42","author":"Dorfman","year":"2011","journal-title":"J Mol Histol"},{"issue":"12","key":"2020071611592304900_B41","doi-asserted-by":"crossref","first-page":"5498","DOI":"10.1210\/en.2009-0679","article-title":"Gonadotropin-releasing hormone neuroterminals and their microenvironment in the median eminence: effects of aging and estradiol treatment","volume":"150","author":"Yin","year":"2009","journal-title":"Endocrinology"},{"issue":"3","key":"2020071611592304900_B42","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1002\/cne.22156","article-title":"Three-dimensional properties of GnRH neuroterminals in the median eminence of young and old rats","volume":"517","author":"Yin","year":"2009","journal-title":"J Comp Neurol"},{"issue":"2","key":"2020071611592304900_B43","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/0304-3940(92)90102-D","article-title":"Ultrastructural characterization of gonadotropin-releasing hormone (GnRH)-immunoreactive terminal nerve cells in the dwarf gourami","volume":"140","author":"Oka","year":"1992","journal-title":"Neurosci Lett"},{"issue":"7048","key":"2020071611592304900_B44","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/nature03875","article-title":"Common mechanisms of nerve and blood vessel wiring","volume":"436","author":"Carmeliet","year":"2005","journal-title":"Nature"},{"issue":"3","key":"2020071611592304900_B45","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1007\/BF00214805","article-title":"Extravascular circulation in the pituitary of Mugil cephalus (Teleostei)","volume":"225","author":"Abraham","year":"1982","journal-title":"Cell Tissue Res"},{"issue":"3","key":"2020071611592304900_B46","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/BF00219143","article-title":"The extravascular channel system in the rostral pituitary of Mugil cephalus (Teleostei) as revealed by use of horseradish peroxidase","volume":"167","author":"Abraham","year":"1976","journal-title":"Cell Tissue Res"},{"issue":"1","key":"2020071611592304900_B47","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/BF00237730","article-title":"Organization and development of the perivascular space system in the neurohypophysis of the laboratory mouse","volume":"199","author":"Enemar","year":"1979","journal-title":"Cell Tissue Res"},{"issue":"1\u20134","key":"2020071611592304900_B48","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/S0044-8486(01)00584-1","article-title":"Endocrine manipulations of spawning in cultured fish: from hormones to genes","volume":"197","author":"Zohar","year":"2001","journal-title":"Aquaculture"},{"issue":"3","key":"2020071611592304900_B49","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.ygcen.2009.03.007","article-title":"Broodstock management and hormonal manipulations of fish reproduction","volume":"165","author":"Mylonas","year":"2010","journal-title":"Gen Comp Endocrinol"},{"issue":"3\u20134","key":"2020071611592304900_B50","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1016\/j.ceca.2011.11.007","article-title":"Coordination of calcium signals by pituitary endocrine cells in situ","volume":"51","author":"Hodson","year":"2012","journal-title":"Cell Calcium"},{"key":"2020071611592304900_B51","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1038\/ncomms1612","article-title":"Existence of long-lasting experience-dependent plasticity in endocrine cell networks","volume":"3","author":"Hodson","year":"2012","journal-title":"Nat Commun"},{"issue":"3","key":"2020071611592304900_B52","doi-asserted-by":"crossref","first-page":"1048","DOI":"10.1210\/en.2004-1415","article-title":"Electrotonic coupling in the anterior pituitary of a teleost fish","volume":"146","author":"Levavi-Sivan","year":"2005","journal-title":"Endocrinology"},{"issue":"2","key":"2020071611592304900_B53","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1210\/en.2013-1642","article-title":"Whole brain-pituitary in vitro preparation of the transgenic medaka (Oryzias latipes) as a tool for analyzing the differential regulatory mechanisms of LH and FSH release","volume":"155","author":"Karigo","year":"2014","journal-title":"Endocrinology"},{"issue":"3","key":"2020071611592304900_B54","first-page":"577","article-title":"The dopaminergic innervation of the goldfish pituitary. An immunocytochemical study at the electron-microscope level using antibodies against dopamine","volume":"244","author":"Kah","year":"1986","journal-title":"Cell Tissue Res"},{"issue":"2","key":"2020071611592304900_B55","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1210\/en.2012-1759","article-title":"Dopamine inhibits reproduction in female zebrafish (Danio rerio) via three pituitary D2 receptor subtypes","volume":"154","author":"Fontaine","year":"2013","journal-title":"Endocrinology"},{"issue":"12","key":"2020071611592304900_B56","doi-asserted-by":"crossref","first-page":"4868","DOI":"10.1210\/en.2014-1472","article-title":"Kiss1 neurons drastically change their firing activity in accordance with the reproductive state: insights from a seasonal breeder","volume":"155","author":"Hasebe","year":"2014","journal-title":"Endocrinology"},{"issue":"4","key":"2020071611592304900_B57","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1095\/biolreprod.107.066266","article-title":"Molecular identification and functional characterization of the kisspeptin\/kisspeptin receptor system in lower vertebrates","volume":"79","author":"Biran","year":"2008","journal-title":"Biol Reprod"},{"issue":"11","key":"2020071611592304900_B58","doi-asserted-by":"crossref","first-page":"4391","DOI":"10.1210\/en.2013-2047","article-title":"LPXRFa, the piscine ortholog of GnIH, and LPXRF-receptor positively regulate gonadotropin secretion in tilapia (Oreochromis niloticus)","volume":"155","author":"Biran","year":"2014","journal-title":"Endocrinology"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/156\/11\/4163\/8989186\/endo4163.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/156\/11\/4163\/8989186\/endo4163.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,7,16]],"date-time":"2020-07-16T18:22:54Z","timestamp":1594923774000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/156\/11\/4163\/2422898"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,8,11]]},"references-count":58,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2015,11,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2015-1150","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"value":"0013-7227","type":"print"},{"value":"1945-7170","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,8,11]]}}}