Background: Kisspeptins are important regulators of the development and function of the hypothalamic-pituitary-gonadal axis. However, the importance of kisspeptin at the pituitary level is unclear. Methods: We examined the expression profile of kisspeptin in the mouse pituitary during development and in adulthood using RT-PCR, quantitative PCR and immunohistochemistry. Results: Kiss1 mRNA was detected in both embryonic and postnatal pituitaries. Kisspeptin-immunoreactive (+) cells were detected from embryonic day (E) 13.5 throughout adulthood, being localized to the rostroventral portion in the anterior pituitary (AP) in embryos, and also to the dorsocaudal AP postnatally. A large proportion of kisspeptin+ cells were double-labeled with gonadotrope markers including Foxl2, SF-1, and LHβ, and the percentage of LHβ+ cells in kisspeptin+ cells increased during development. No kisspeptin+ cells were positive for the proliferating cell marker MCM7 (minichromosome maintenance protein 7), but a few kisspeptin+ cells co-expressed the stem/progenitor cell marker Sox2. Kisspeptin expression was similar between sexes and between agonadal SF-1 knockout embryos and wild-type littermates. Kiss1 mRNA levels were not significantly different between sexes or during early postnatal development, but levels in females increased when puberty began and were significantly higher than in males at postpubertal ages. Conclusions: These results suggest that kisspeptin is expressed in gonadotrope precursors during gonadotrope differentiation, and that kisspeptin expression begins soon after the initiation of αGSU production and is extinguished soon after the initiation of LH production. Furthermore, pituitary kisspeptin expression may be regulated in a gonad-independent manner during development, but may be associated with gonadotrope function in adulthood.

1.
Kauffman AS: Gonadal and nongonadal regulation of sex differences in hypothalamic Kiss1 neurones. J Neuroendocrinol 2010;22:682-691.
2.
Pinilla L, Aguilar E, Dieguez C, Millar RP, Tena-Sempere M: Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiol Rev 2012;92:1235-1316.
3.
Bhattacharya M, Babwah AV: Kisspeptin: beyond the brain. Endocrinology 2015;156:1218-1227.
4.
Brock O, Bakker J: The two kisspeptin neuronal populations are differentially organized and activated by estradiol in mice. Endocrinology 2013;154:2739-2749.
5.
Luo X, Ikeda Y, Parker KL: A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 1994;77:481-490.
6.
Knoll JG, Clay CM, Bouma GJ, Henion TR, Schwarting GA, Millar RP, Tobet SA: Developmental profile and sexually dimorphic expression of kiss1 and kiss1r in the fetal mouse brain. Front Endocrinol 2013;4:140.
7.
Desroziers E, Droguerre M, Bentsen AH, Robert V, Mikkelsen JD, Caraty A, Tillet Y, Duittoz A, Franceschini I: Embryonic development of kisspeptin neurones in rat. J Neuroendocrinol 2012;24:1284-1295.
8.
Kumar D, Periasamy V, Freese M, Voigt A, Boehm U: In utero development of kisspeptin/GnRH neural circuitry in male mice. Endocrinology 2015;156:3084-3090.
9.
Kauffman AS, Clifton DK, Steiner RA: Emerging ideas about kisspeptin-GPR54 signaling in the neuroendocrine regulation of reproduction. Trends Neurosci 2007;30:504-511.
10.
Matsui H, Takatsu Y, Kumano S, Matsumoto H, Ohtaki T: Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun 2004;320:383-388.
11.
Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM: Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci USA 2005;102:2129-2134.
12.
Navarro VM, Castellano JM, Fernández-Fernández R, Tovar S, Roa J, Mayen A, Barreiro ML, Casanueva FF, Aguilar E, Dieguez C, Pinilla L, Tena-Sempere M: Effects of KiSS-1 peptide, the natural ligand of GPR54, on follicle-stimulating hormone secretion in the rat. Endocrinology 2005;146:1689-1697.
13.
Gutiérrez-Pascual E, Martínez-Fuentes AJ, Pinilla L, Tena-Sempere M, Malagón MM, Castaño JP: Direct pituitary effects of kisspeptin: activation of gonadotrophs and somatotrophs and stimulation of luteinising hormone and growth hormone secretion. J Neuroendocrinol 2007;19:521-530.
14.
Suzuki S, Kadokawa H, Hashizume T: Direct kisspeptin-10 stimulation on luteinizing hormone secretion from bovine and porcine anterior pituitary cells. Anim Reprod Sci 2008;103:360-365.
15.
Witham EA, Meadows JD, Hoffmann HM, Shojaei S, Coss D, Kauffman AS, Mellon PL: Kisspeptin regulates gonadotropin genes via immediate early gene induction in pituitary gonadotropes. Mol Endocrinol 2013;27:1283-1294.
16.
Jeyasuria P, Ikeda Y, Jamin SP, Zhao L, De Rooij DG, Themmen AP, Behringer RR, Parker KL: Cell-specific knockout of steroidogenic factor 1 reveals its essential roles in gonadal function. Mol Endocrinol 2004;18:1610-1619.
17.
Ellsworth BS, Egashira N, Haller JL, Butts DL, Cocquet J, Clay CM, Osamura RY, Camper SA: FOXL2 in the pituitary: molecular, genetic, and developmental analysis. Mol Endocrinol 2006;20:2796-2805.
18.
Sornson MW, Wu W, Dasen JS, Flynn SE, Norman DJ, O'Connell SM, Gukovsky I, Carriere C, Ryan AK, Miller AP, Zuo L, Gleiberman AS, Andersen B, Beamer WG, Rosenfeld MG: Pituitary lineage determination by the Prophet of Pit-1 homeodomain factor defective in Ames dwarfism. Nature 1996;384:327-333.
19.
Fauquier T, Rizzoti K, Dattani M, Lovell-Badge R, Robinson IC: SOX2-expressing progenitor cells generate all of the major cell types in the adult mouse pituitary gland. Proc Natl Acad Sci USA 2008;105:2907-2912.
20.
Andoniadou CL, Matsushima D, Mousavy Gharavy SN, Signore M, Mackintosh AI, Schaeffer M, Gaston-Massuet C, Mollard P, Jacques TS, Le Tissier P, Dattani MT, Pevny LH, Martinez-Barbera JP: Sox2+ stem/progenitor cells in the adult mouse pituitary support organ homeostasis and have tumor-inducing potential. Cell Stem Cell 2013;13:433-445.
21.
Rizzoti K, Akiyama H, Lovell-Badge R: Mobilized adult pituitary stem cells contribute to endocrine regeneration in response to physiological demand. Cell Stem Cell 2013;13:419-432.
22.
Devnath S, Inoue K: An insight to pituitary folliculo-stellate cells. J Neuroendocrinol 2008;20:687-691.
23.
Scully KM, Rosenfeld MG: Pituitary development: regulatory codes in mammalian organogenesis. Science 2002;295:2231-2235.
24.
Zhu X, Gleiberman AS, Rosenfeld MG: Molecular physiology of pituitary development: signaling and transcriptional networks. Physiol Rev 2007;87:933-963.
25.
Ikeda Y, Takeda Y, Shikayama T, Mukai T, Hisano S, Morohashi KI: Comparative localization of Dax-1 and Ad4BP/SF-1 during development of the hypothalamic-pituitary-gonadal axis suggests their closely related and distinct functions. Dev Dyn 2001;220:363-376.
26.
Park S, Mullen RD, Rhodes SJ: Cell-specific actions of a human LHX3 gene enhancer during pituitary and spinal cord development. Mol Endocrinol 2013;27:2013-2027.
27.
Lin SC, Li S, Drolet DW, Rosenfeld MG: Pituitary ontogeny of the Snell dwarf mouse reveals Pit-1-independent and Pit-1-dependent origins of the thyrotrope. Development 1994;120:515-522.
28.
Vankelecom H: Pituitary stem/progenitor cells: embryonic players in the adult gland? Eur J Neurosci 2010;32:2063-2081.
29.
Gremeaux L, Fu Q, Chen J, Vankelecom H: Activated phenotype of the pituitary stem/progenitor cell compartment during the early-postnatal maturation phase of the gland. Stem Cells Dev 2012;21:801-813.
30.
Richard N, Galmiche G, Corvaisier S, Caraty A, Kottler ML: KiSS-1 and GPR54 genes are co-expressed in rat gonadotrophs and differentially regulated in vivo by oestradiol and gonadotrophin-releasing hormone. J Neuroendocrinol 2008;20:381-393.
31.
Castinetti F, Davis SW, Brue T, Camper SA: Pituitary stem cell update and potential implications for treating hypopituitarism. Endocr Rev 2011;32:453-471.
32.
Ingraham HA, Lala DS, Ikeda Y, Luo X, Shen WH, Nachtigal MW, Abbud R, Nilson JH, Parker KL: The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes Dev 1994;8:2302-2312.
33.
Funes S, Hedrick JA, Vassileva G, Markowitz L, Abbondanzo S, Golovko A, Yang S, Monsma FJ, Gustafson EL: The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem Biophys Res Commun 2003;312:1357-1363.
34.
Lapatto R, Pallais JC, Zhang D, Chan YM, Mahan A, Cerrato F, Le WW, Hoffman GE, Seminara SB: Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice. Endocrinology 2007;148:4927-4936.
35.
d'Anglemont de Tassigny X, Fagg LA, Carlton MB, Colledge WH: Kisspeptin can stimulate gonadotropin-releasing hormone (GnRH) release by a direct action at GnRH nerve terminals. Endocrinology 2008;149:3926-3932.
36.
Kirilov M, Clarkson J, Liu X, Roa J, Campos P, Porteous R, Schütz G, Herbison AE: Dependence of fertility on kisspeptin-Gpr54 signaling at the GnRH neuron. Nat Commun 2013;4:2492.
37.
Novaira HJ, Sonko ML, Hoffman G, Koo Y, Ko C, Wolfe A, Radovick S: Disrupted kisspeptin signaling in GnRH neurons leads to hypogonadotrophic hypogonadism. Mol Endocrinol 2014;28:225-238.
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