The Development of Kisspeptin Circuits in the Mammalian Brain

  • Sheila J. Semaan
  • Kristen P. Tolson
  • Alexander S. Kauffman
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 784)


The neuropeptide kisspeptin, encoded by the Kiss1 gene, is required for mammalian puberty and fertility. Examining the development of the kisspeptin system contributes to our understanding of pubertal progression and adult reproduction and sheds light on possible mechanisms underlying the development of reproductive disorders, such as precocious puberty or hypogonadotropic hypogonadism. Recent work, primarily in rodent models, has begun to study the development of kisspeptin neurons and their regulation by sex steroids and other factors at early life stages. In the brain, kisspeptin is predominantly expressed in two areas of the hypothalamus, the anteroventral periventricular nucleus and neighboring periventricular nucleus (pre-optic area in some species) and the arcuate nucleus. Kisspeptin neurons in these two hypothalamic regions are differentially regulated by testosterone and estradiol, both in development and in adulthood, and also display differences in their degree of sexual dimorphism. In this chapter, we discuss what is currently known and not known about the ontogeny, maturation, and sexual differentiation of kisspeptin neurons, as well as their regulation by sex steroids and other factors during development.


GnRH Neuron Luteinizing Hormone Surge ArKO Mouse Kiss1 Gene Kiss1 mRNA 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Cesario SK, Hughes LA (2007) Precocious puberty: a comprehensive review of literature. J Obstet Gynecol Neonatal Nurs 36:263–274PubMedCrossRefGoogle Scholar
  2. 2.
    Fechner A, Fong S, McGovern P (2008) A review of Kallmann syndrome: genetics, pathophysiology, and clinical management. Obstet Gynecol Surv 63:189–194PubMedCrossRefGoogle Scholar
  3. 3.
    Bianco SD, Kaiser UB (2009) The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism. Nat Rev Endocrinol 5:569–576PubMedCrossRefGoogle Scholar
  4. 4.
    Fechner PY (2002) Gender differences in puberty. J Adolesc Health 30:44–48PubMedCrossRefGoogle Scholar
  5. 5.
    Semaan SJ, Kauffman AS (2010) Sexual differentiation and development of forebrain reproductive circuits. Curr Opin Neurobiol 20:424–431PubMedCrossRefGoogle Scholar
  6. 6.
    Kauffman AS (2010) Coming of age in the kisspeptin era: sex differences, development, and puberty. Mol Cell Endocrinol 324:51–63PubMedCrossRefGoogle Scholar
  7. 7.
    Clarkson J, d’Anglemont de Tassigny X, Moreno AS, Colledge WH, Herbison AE (2008) Kisspeptin-GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. J Neurosci 28:8691–8697PubMedCrossRefGoogle Scholar
  8. 8.
    Pineda R, Garcia-Galiano D, Roseweir A, Romero M, Sanchez-Garrido MA, Ruiz-Pino F, Morgan K, Pinilla L, Millar RP, Tena-Sempere M (2009) Critical roles of kisspeptins in female puberty and preovulatory gonadotropin surges as revealed by a novel antagonist. Endocrinology 151(2):722–730PubMedCrossRefGoogle Scholar
  9. 9.
    Cravo RM, Margatho LO, Osborne-Lawrence S, Donato J Jr, Atkin S, Bookout AL, Rovinsky S, Frazao R, Lee CE, Gautron L, Zigman JM, Elias CF (2011) Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience 173:37–56PubMedCrossRefGoogle Scholar
  10. 10.
    Mayer C, Acosta-Martinez M, Dubois SL, Wolfe A, Radovick S, Boehm U, Levine JE (2010) Timing and completion of puberty in female mice depend on estrogen receptor alpha-­signaling in kisspeptin neurons. Proc Natl Acad Sci USA 107:22693–22698PubMedCrossRefGoogle Scholar
  11. 11.
    Gottsch ML, Popa SM, Lawhorn JK, Qiu J, Tonsfeldt KJ, Bosch MA, Kelly MJ, Ronnekleiv OK, Sanz E, McKnight GS, Clifton DK, Palmiter RD, Steiner RA (2011) Molecular ­properties of Kiss1 neurons in the arcuate nucleus of the mouse. Endocrinology 152:4298–4309PubMedCrossRefGoogle Scholar
  12. 12.
    Navarro VM, Castellano JM, Fernández-Fernández R, Barreiro ML, Roa J, Sanchez-Criado JE, Aguilar E, Dieguez C, Pinilla L, Tena-Sempere M (2004) Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide. Endocrinology 145:4565–4574PubMedCrossRefGoogle Scholar
  13. 13.
    Brailoiu GC, Dun SL, Ohsawa M, Yin D, Yang J, Chang JK, Brailoiu E, Dun NJ (2005) KiSS-1 expression and metastin-like immunoreactivity in the rat brain. J Comp Neurol 481:314–329PubMedCrossRefGoogle Scholar
  14. 14.
    Clarkson J, D’Anglemont de Tassigny X, Colledge WH, Caraty A, Herbison AE (2009) Distribution of kisspeptin neurones in the adult female mouse brain. J Neuroendocrinol 21:673–682PubMedCrossRefGoogle Scholar
  15. 15.
    Franceschini I, Lomet D, Cateau M, Delsol G, Tillet Y, Caraty A (2006) Kisspeptin immunoreactive cells of the ovine preoptic area and arcuate nucleus co-express estrogen receptor alpha. Neurosci Lett 401:225–230PubMedCrossRefGoogle Scholar
  16. 16.
    Goodman RL, Lehman MN, Smith JT, Coolen LM, de Oliveira CV, Jafarzadehshirazi MR, Pereira A, Iqbal J, Caraty A, Ciofi P, Clarke IJ (2007) Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology 148:5752–5760PubMedCrossRefGoogle Scholar
  17. 17.
    Greives TJ, Mason AO, Scotti MA, Levine J, Ketterson ED, Kriegsfeld LJ, Demas GE (2007) Environmental control of kisspeptin: implications for seasonal reproduction. Endocrinology 148:1158–1166PubMedCrossRefGoogle Scholar
  18. 18.
    Ohkura S, Takase K, Matsuyama S, Mogi K, Ichimaru T, Wakabayashi Y, Uenoyama Y, Mori Y, Steiner RA, Tsukamura H, Maeda KI, Okamura H (2009) Gonadotrophin-releasing hormone pulse generator activity in the hypothalamus of the goat. J Neuroendocrinol 21:813–821PubMedCrossRefGoogle Scholar
  19. 19.
    Ramaswamy S, Guerriero KA, Gibbs RB, Plant TM (2008) Structural interactions between kisspeptin and GnRH neurons in the mediobasal hypothalamus of the male rhesus monkey (Macaca mulatta) as revealed by double immunofluorescence and confocal microscopy. Endocrinology 149:4387–4395PubMedCrossRefGoogle Scholar
  20. 20.
    Kim J, Semaan SJ, Clifton DK, Steiner RA, Dhamija S, Kauffman AS (2011) Regulation of Kiss1 expression by sex steroids in the amygdala of the rat and mouse. Endocrinology 152:2020–2030PubMedCrossRefGoogle Scholar
  21. 21.
    Gottsch ML, Cunningham MJ, Smith JT, Popa SM, Acohido BV, Crowley WF, Seminara S, Clifton DK, Steiner RA (2004) A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 145:4073–4077PubMedCrossRefGoogle Scholar
  22. 22.
    Smith JT, Cunningham MJ, Rissman EF, Clifton DK, Steiner RA (2005) Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 146:3686–3692PubMedCrossRefGoogle Scholar
  23. 23.
    Kauffman AS, Park JH, McPhie-Lalmansingh AA, Gottsch ML, Bodo C, Hohmann JG, Pavlova MN, Rohde AD, Clifton DK, Steiner RA, Rissman EF (2007) The kisspeptin receptor GPR54 is required for sexual differentiation of the brain and behavior. J Neurosci 27:8826–8835PubMedCrossRefGoogle Scholar
  24. 24.
    Smith JT, Clay CM, Caraty A, Clarke IJ (2007) KiSS-1 messenger ribonucleic acid expression in the hypothalamus of the ewe is regulated by sex steroids and season. Endocrinology 148:1150–1157PubMedCrossRefGoogle Scholar
  25. 25.
    Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM (2005) Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci USA 102:2129–2134PubMedCrossRefGoogle Scholar
  26. 26.
    Kim W, Jessen HM, Auger AP, Terasawa E (2009) Postmenopausal increase in KiSS-1, GPR54, and luteinizing hormone releasing hormone (LHRH-1) mRNA in the basal hypothalamus of female rhesus monkeys. Peptides 30:103–110PubMedCrossRefGoogle Scholar
  27. 27.
    Smith JT, Shahab M, Pereira A, Pau KY, Clarke IJ (2010) Hypothalamic expression of KISS1 and gonadotropin inhibitory hormone genes during the menstrual cycle of a non-human primate. Biol Reprod 83:568–577PubMedCrossRefGoogle Scholar
  28. 28.
    Clarkson J, Herbison AE (2006) Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology 147:5817–5825PubMedCrossRefGoogle Scholar
  29. 29.
    Yeo SH, Herbison AE (2011) Projections of arcuate nucleus and rostral periventricular kisspeptin neurons in the adult female mouse brain. Endocrinology 152:2387–2399PubMedCrossRefGoogle Scholar
  30. 30.
    Smith JT, Li Q, Yap KS, Shahab M, Roseweir AK, Millar RP, Clarke IJ (2011) Kisspeptin is essential for the full preovulatory LH surge and stimulates GnRH release from the isolated ovine median eminence. Endocrinology 152:1001–1012PubMedCrossRefGoogle Scholar
  31. 31.
    Kauffman AS (2009) Sexual differentiation and the Kiss1 system: hormonal and developmental considerations. Peptides 30:83–93PubMedCrossRefGoogle Scholar
  32. 32.
    Simerly RB (2002) Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain. Annu Rev Neurosci 25:507–536PubMedCrossRefGoogle Scholar
  33. 33.
    Herbison AE (2008) Estrogen positive feedback to gonadotropin-releasing hormone (GnRH) neurons in the rodent: the case for the rostral periventricular area of the third ventricle (RP3V). Brain Res Rev 57:277–287PubMedCrossRefGoogle Scholar
  34. 34.
    Smith JT, Popa SM, Clifton DK, Hoffman GE, Steiner RA (2006) Kiss1 neurons in the forebrain as central processors for generating the preovulatory luteinizing hormone surge. J Neurosci 26:6687–6694PubMedCrossRefGoogle Scholar
  35. 35.
    Robertson JL, Clifton DK, de la Iglesia HO, Steiner RA, Kauffman AS (2009) Circadian regulation of Kiss1 neurons: implications for timing the preovulatory gonadotropin-releasing hormone/luteinizing hormone surge. Endocrinology 150:3664–3671PubMedCrossRefGoogle Scholar
  36. 36.
    Kauffman AS, Gottsch ML, Roa J, Byquist AC, Crown A, Clifton DK, Hoffman GE, Steiner RA, Tena-Sempere M (2007) Sexual differentiation of Kiss1 gene expression in the brain of the rat. Endocrinology 148:1774–1783PubMedCrossRefGoogle Scholar
  37. 37.
    Simerly RB (1998) Organization and regulation of sexually dimorphic neuroendocrine pathways. Behav Brain Res 92:195–203PubMedCrossRefGoogle Scholar
  38. 38.
    Simerly RB, Zee MC, Pendleton JW, Lubahn DB, Korach KS (1997) Estrogen receptor-­dependent sexual differentiation of dopaminergic neurons in the preoptic region of the mouse. Proc Natl Acad Sci USA 94:14077–14082PubMedCrossRefGoogle Scholar
  39. 39.
    Ottem EN, Godwin JG, Krishnan S, Petersen SL (2004) Dual-phenotype GABA/glutamate neurons in adult preoptic area: sexual dimorphism and function. J Neurosci 24:8097–8105PubMedCrossRefGoogle Scholar
  40. 40.
    Semaan SJ, Murray EK, Poling MC, Dhamija S, Forger NG, Kauffman AS (2010) BAX-­dependent and BAX-independent regulation of Kiss1 neuron development in mice. Endocrinology 151:5807–5817PubMedCrossRefGoogle Scholar
  41. 41.
    Clarkson J, Herbison AE (2011) Dual phenotype kisspeptin-dopamine neurones of the rostral periventricular area of the third ventricle project to gonadotrophin-releasing hormone neurones. J Neuroendocrinol 23:293–301PubMedCrossRefGoogle Scholar
  42. 42.
    Adachi S, Yamada S, Takatsu Y, Matsui H, Kinoshita M, Takase K, Sugiura H, Ohtaki T, Matsumoto H, Uenoyama Y, Tsukamura H, Inoue K, Maeda K (2007) Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats. J Reprod Dev 53:367–378PubMedCrossRefGoogle Scholar
  43. 43.
    Rometo AM, Krajewski SJ, Voytko ML, Rance NE (2007) Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys. J Clin Endocrinol Metab 92:2744–2750PubMedCrossRefGoogle Scholar
  44. 44.
    Kauffman AS, Navarro VM, Kim J, Clifton DK, Steiner RA (2009) Sex differences in the regulation of Kiss1/NKB neurons in juvenile mice: implications for the timing of puberty. Am J Physiol Endocrinol Metab 297:E1212–E1221PubMedCrossRefGoogle Scholar
  45. 45.
    Smith JT (2008) Kisspeptin signalling in the brain: steroid regulation in the rodent and ewe. Brain Res Rev 57:288–298PubMedCrossRefGoogle Scholar
  46. 46.
    Smith JT, Dungan HM, Stoll EA, Gottsch ML, Braun RE, Eacker SM, Clifton DK, Steiner RA (2005) Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology 146:2976–2984PubMedCrossRefGoogle Scholar
  47. 47.
    Cao J, Patisaul HB (2011) Sexually dimorphic expression of hypothalamic estrogen receptors alpha and beta and Kiss1 in neonatal male and female rats. J Comp Neurol 519:2954–2977PubMedCrossRefGoogle Scholar
  48. 48.
    Shughrue PJ, Merchenthaler I (2001) Distribution of estrogen receptor beta immunoreactivity in the rat central nervous system. J Comp Neurol 436:64–81PubMedCrossRefGoogle Scholar
  49. 49.
    Simerly RB, Chang C, Muramatsu M, Swanson LW (1990) Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study. J Comp Neurol 294:76–95PubMedCrossRefGoogle Scholar
  50. 50.
    Oakley AE, Clifton DK, Steiner RA (2009) Kisspeptin signaling in the brain. Endocr Rev 30:713–743PubMedCrossRefGoogle Scholar
  51. 51.
    Smith JT (2009) Sex steroid control of hypothalamic Kiss1 expression in sheep and rodents: comparative aspects. Peptides 30:94–102PubMedCrossRefGoogle Scholar
  52. 52.
    Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Ozbek MN, Imamoglu S, Akalin NS, Yuksel B, O’Rahilly S, Semple RK (2009) TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for neurokinin B in the central control of reproduction. Nat Genet 41:354–358PubMedCrossRefGoogle Scholar
  53. 53.
    Goodman RL, Coolen LM, Anderson GM, Hardy SL, Valent M, Connors JM, Fitzgerald ME, Lehman MN (2004) Evidence that dynorphin plays a major role in mediating progesterone negative feedback on gonadotropin-releasing hormone neurons in sheep. Endocrinology 145:2959–2967PubMedCrossRefGoogle Scholar
  54. 54.
    Kinoshita M, Tsukamura H, Adachi S, Matsui H, Uenoyama Y, Iwata K, Yamada S, Inoue K, Ohtaki T, Matsumoto H, Maeda K (2005) Involvement of central metastin in the regulation of preovulatory luteinizing hormone surge and estrous cyclicity in female rats. Endocrinology 146:4431–4436PubMedCrossRefGoogle Scholar
  55. 55.
    Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA (2009) Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J Neurosci 29:11859–11866PubMedCrossRefGoogle Scholar
  56. 56.
    Sandoval-Guzman T, Rance NE (2004) Central injection of senktide, an NK3 receptor agonist, or neuropeptide Y inhibits LH secretion and induces different patterns of Fos expression in the rat hypothalamus. Brain Res 1026:307–312PubMedCrossRefGoogle Scholar
  57. 57.
    Schulz R, Wilhelm A, Pirke KM, Gramsch C, Herz A (1981) Beta-endorphin and dynorphin control serum luteinizing hormone level in immature female rats. Nature 294:757–759PubMedCrossRefGoogle Scholar
  58. 58.
    Burke MC, Letts PA, Krajewski SJ, Rance NE (2006) Coexpression of dynorphin and neurokinin B immunoreactivity in the rat hypothalamus: morphologic evidence of interrelated function within the arcuate nucleus. J Comp Neurol 498:712–726PubMedCrossRefGoogle Scholar
  59. 59.
    Foradori CD, Amstalden M, Goodman RL, Lehman MN (2006) Colocalisation of dynorphin a and neurokinin B immunoreactivity in the arcuate nucleus and median eminence of the sheep. J Neuroendocrinol 18:534–541PubMedCrossRefGoogle Scholar
  60. 60.
    Krajewski SJ, Burke MC, Anderson MJ, McMullen NT, Rance NE (2010) Forebrain projections of arcuate neurokinin B neurons demonstrated by anterograde tract-tracing and monosodium glutamate lesions in the rat. Neuroscience 166:680–697PubMedCrossRefGoogle Scholar
  61. 61.
    Desroziers E, Droguerre M, Bentsen AH, Robert V, Mikkelsen JD, Caraty A, Tillet Y, Duittoz A, Franceschini I (2012) Embryonic development of kisspeptin neurones in rat. J Neuroendocrinol 24(10):1284–1295PubMedCrossRefGoogle Scholar
  62. 62.
    Clarkson J, Boon WC, Simpson ER, Herbison AE (2009) Postnatal development of an estradiol-­kisspeptin positive feedback mechanism implicated in puberty onset. Endocrinology 150:3214–3220PubMedCrossRefGoogle Scholar
  63. 63.
    Kauffman AS, Semaan SJ (2011) Pubertal changes in gene expression in reproductive neural circuits of female mice. Society for Neuroscience: Abstract #713Google Scholar
  64. 64.
    Takumi K, Iijima N, Ozawa H (2011) Developmental changes in the expression of kisspeptin mRNA in rat hypothalamus. J Mol Neurosci 43:138–145PubMedCrossRefGoogle Scholar
  65. 65.
    Redmond JS, Baez-Sandoval GM, Spell KM, Spencer TE, Lents CA, Williams GL, Amstalden M (2011) Developmental changes in hypothalamic Kiss1 expression during ­activation of the pulsatile release of luteinising hormone in maturing ewe lambs. J Neuroendocrinol 23:815–822PubMedCrossRefGoogle Scholar
  66. 66.
    Homma T, Sakakibara M, Yamada S, Kinoshita M, Iwata K, Tomikawa J, Kanazawa T, Matsui H, Takatsu Y, Ohtaki T, Matsumoto H, Uenoyama Y, K-I M, Tsukamura H (2009) Significance of neonatal testicular sex steroids to defeminize anteroventral periventricular kisspeptin neurons and the GnRH/LH surge system in male rats. Biol Reprod 81:1216–1225PubMedCrossRefGoogle Scholar
  67. 67.
    Cheng G, Coolen LM, Padmanabhan V, Goodman RL, Lehman MN (2010) The kisspeptin/neurokinin B/dynorphin (KNDy) cell population of the arcuate nucleus: sex differences and effects of prenatal testosterone in sheep. Endocrinology 151:301–311PubMedCrossRefGoogle Scholar
  68. 68.
    Morris JA, Jordan CL, Breedlove SM (2004) Sexual differentiation of the vertebrate nervous system. Nat Neurosci 7:1034–1039PubMedCrossRefGoogle Scholar
  69. 69.
    Bateman HL, Patisaul HB (2008) Disrupted female reproductive physiology following neonatal exposure to phytoestrogens or estrogen specific ligands is associated with decreased GnRH activation and kisspeptin fiber density in the hypothalamus. Neurotoxicology 29:988–997PubMedCrossRefGoogle Scholar
  70. 70.
    Patisaul HB, Todd KL, Mickens JA, Adewale HB (2009) Impact of neonatal exposure to the ERalpha agonist PPT, bisphenol-A or phytoestrogens on hypothalamic kisspeptin fiber density in male and female rats. Neurotoxicology 30:350–357PubMedCrossRefGoogle Scholar
  71. 71.
    Patisaul HB, Losa-Ward SM, Todd KL, McCaffrey KA, Mickens JA (2012) Influence of ERbeta selective agonism during the neonatal period on the sexual differentiation of the rat hypothalamic-pituitary-gonadal (HPG) axis. Biol Sex Differ 3:2PubMedCrossRefGoogle Scholar
  72. 72.
    Forger NG (2009) Control of cell number in the sexually dimorphic brain and spinal cord. J Neuroendocrinol 21:393–399PubMedCrossRefGoogle Scholar
  73. 73.
    McCarthy MM, Auger AP, Bale TL, De Vries GJ, Dunn GA, Forger NG, Murray EK, Nugent BM, Schwarz JM, Wilson ME (2009) The epigenetics of sex differences in the brain. J Neurosci 29:12815–12823PubMedCrossRefGoogle Scholar
  74. 74.
    Murray EK, Hien A, de Vries GJ, Forger NG (2009) Epigenetic control of sexual differentiation of the bed nucleus of the stria terminalis. Endocrinology 150:4241–4247PubMedCrossRefGoogle Scholar
  75. 75.
    Zhang JM, Konkle AT, Zup SL, McCarthy MM (2008) Impact of sex and hormones on new cells in the developing rat hippocampus: a novel source of sex dimorphism? Eur J Neurosci 27:791–800PubMedCrossRefGoogle Scholar
  76. 76.
    Forger NG, Rosen GJ, Waters EM, Jacob D, Simerly RB, de Vries GJ (2004) Deletion of Bax eliminates sex differences in the mouse forebrain. Proc Natl Acad Sci USA 101:13666–13671PubMedCrossRefGoogle Scholar
  77. 77.
    Gotsiridze T, Kang N, Jacob D, Forger NG (2007) Development of sex differences in the principal nucleus of the bed nucleus of the stria terminalis of mice: role of Bax-dependent cell death. Dev Neurobiol 67:355–362PubMedCrossRefGoogle Scholar
  78. 78.
    Krishnan S, Intlekofer KA, Aggison LK, Petersen SL (2009) Central role of TRAF-interacting protein in a new model of brain sexual differentiation. Proc Natl Acad Sci USA 106:16692–16697PubMedCrossRefGoogle Scholar
  79. 79.
    Holmes MM, McCutcheon J, Forger NG (2009) Sex differences in NeuN- and androgen receptor-positive cells in the bed nucleus of the stria terminalis are due to Bax-dependent cell death. Neuroscience 158:1251–1256PubMedCrossRefGoogle Scholar
  80. 80.
    Adams JM, Cory S (2007) The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 26:1324–1337PubMedCrossRefGoogle Scholar
  81. 81.
    Tsukahara S, Kakeyama M, Toyofuku Y (2006) Sex differences in the level of Bcl-2 family proteins and caspase-3 activation in the sexually dimorphic nuclei of the preoptic area in postnatal rats. J Neurobiol 66:1411–1419PubMedCrossRefGoogle Scholar
  82. 82.
    Waters EM, Simerly RB (2009) Estrogen induces caspase-dependent cell death during hypothalamic development. J Neurosci 29:9714–9718PubMedCrossRefGoogle Scholar
  83. 83.
    Semaan SJ, Dhamija S, Kim J, Ku EC, Kauffman AS (2012) Assessment of epigenetic contributions to sexually-dimorphic kiss1 expression in the anteroventral periventricular nucleus of mice. Endocrinology 153:1875–1886PubMedCrossRefGoogle Scholar
  84. 84.
    Nugent BM, McCarthy MM (2010) Epigenetic underpinnings of developmental sex differences in the brain. Neuroendocrinology 93:150–158CrossRefGoogle Scholar
  85. 85.
    Kurian JR, Olesen KM, Auger AP (2010) Sex differences in epigenetic regulation of the estrogen receptor-alpha promoter within the developing preoptic area. Endocrinology 151:2297–2305PubMedCrossRefGoogle Scholar
  86. 86.
    Schwarz JM, Nugent BM, McCarthy MM (2010) Developmental and hormone-induced epigenetic changes to estrogen and progesterone receptor genes in brain are dynamic across the life span. Endocrinology 151:4871–4881PubMedCrossRefGoogle Scholar
  87. 87.
    Matsuda KI, Mori H, Nugent BM, Pfaff DW, McCarthy MM, Kawata M (2011) Histone deacetylation during brain development is essential for permanent masculinization of sexual behavior. Endocrinology 152:2760–2767PubMedCrossRefGoogle Scholar
  88. 88.
    Murray EK, Varnum MM, Fernandez JL, de Vries GJ, Forger NG (2011) Effects of neonatal treatment with valproic acid on vasopressin immunoreactivity and olfactory behaviour in mice. J Neuroendocrinol 23(10):906–914PubMedCrossRefGoogle Scholar
  89. 89.
    Goldberg AD, Allis CD, Bernstein E (2007) Epigenetics: a landscape takes shape. Cell 128:635–638PubMedCrossRefGoogle Scholar
  90. 90.
    Kolodkin MH, Auger AP (2011) Sex difference in the expression of DNA methyltransferase 3a in the rat amygdala during development. J Neuroendocrinol 23:577–583PubMedCrossRefGoogle Scholar
  91. 91.
    Takase K, Uenoyama Y, Inoue N, Matsui H, Yamada S, Shimizu M, Homma T, Tomikawa J, Kanda S, Matsumoto H, Oka Y, Tsukamura H, Maeda KI (2009) Possible role of oestrogen in pubertal increase of Kiss1/kisspeptin expression in discrete hypothalamic areas of female rats. J Neuroendocrinol 21:527–537PubMedCrossRefGoogle Scholar
  92. 92.
    Bakker J, Pierman S, Gonzalez-Martinez D (2010) Effects of aromatase mutation (ArKO) on the sexual differentiation of kisspeptin neuronal numbers and their activation by same versus opposite sex urinary pheromones. Horm Behav 57:390–395PubMedCrossRefGoogle Scholar
  93. 93.
    Cattanach BM, Iddon CA, Charlton HM, Chiappa SA, Fink G (1977) Gonadotrophin-­releasing hormone deficiency in a mutant mouse with hypogonadism. Nature 269:338–340PubMedCrossRefGoogle Scholar
  94. 94.
    Gill JC, Wang O, Kakar S, Martinelli E, Carroll RS, Kaiser UB (2010) Reproductive hormone-­dependent and -independent contributions to developmental changes in kisspeptin in GnRH-deficient hypogonadal mice. PLoS One 5:e11911PubMedCrossRefGoogle Scholar
  95. 95.
    Dickerson SM, Cunningham SL, Patisaul HB, Woller MJ, Gore AC (2010) Endocrine disruption of brain sexual differentiation by developmental PCB exposure. Endocrinology 152:581–594PubMedCrossRefGoogle Scholar
  96. 96.
    Tena-Sempere M (2010) Kisspeptin/GPR54 system as potential target for endocrine disruption of reproductive development and function. Int J Androl 33:360–368PubMedCrossRefGoogle Scholar
  97. 97.
    Desroziers E, Mikkelsen JD, Duittoz A, Franceschini I (2012) Kisspeptin-immunoreactivity changes in a sex- and hypothalamic-region-specific manner across rat postnatal development. J Neuroendocrinol 24:1154–1165PubMedCrossRefGoogle Scholar
  98. 98.
    Poling MC, Kauffman AS (2012) Sexually dimorphic testosterone secretion in prenatal and neonatal mice is independent of kisspeptin-kiss1r and GnRH signaling. Endocrinology 153:782–793PubMedCrossRefGoogle Scholar
  99. 99.
    Cao J, Mickens JA, McCaffrey KA, Leyrer SM, Patisaul HB (2012) Neonatal bisphenol A exposure alters sexually dimorphic gene expression in the postnatal rat hypothalamus. Neurotoxicology 33:23–36PubMedCrossRefGoogle Scholar
  100. 100.
    Herbison AE, de Tassigny X, Doran J, Colledge WH (2010) Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin-releasing hormone neurons. Endocrinology 151:312–321PubMedCrossRefGoogle Scholar
  101. 101.
    Corbier P (1985) Sexual differentiation of positive feedback: effect of hour of castration at birth on estradiol-induced luteinizing hormone secretion in immature male rats. Endocrinology 116:142–147PubMedCrossRefGoogle Scholar
  102. 102.
    Corbier P, Edwards DA, Roffi J (1992) The neonatal testosterone surge: a comparative study. Arch Int Physiol Biochim Biophys 100:127–131PubMedCrossRefGoogle Scholar
  103. 103.
    Corbier P, Kerdelhue B, Picon R, Roffi J (1978) Changes in testicular weight and serum gonadotropin and testosterone levels before, during, and after birth in the perinatal rat. Endocrinology 103:1985–1991PubMedCrossRefGoogle Scholar
  104. 104.
    Motelica-Heino I, Castanier M, Corbier P, Edwards DA, Roffi J (1988) Testosterone levels in plasma and testes of neonatal mice. J Steroid Biochem 31:283–286PubMedCrossRefGoogle Scholar
  105. 105.
    Baum MJ, Brand T, Ooms M, Vreeburg JT, Slob AK (1988) Immediate postnatal rise in whole body androgen content in male rats: correlation with increased testicular content and reduced body clearance of testosterone. Biol Reprod 38:980–986PubMedCrossRefGoogle Scholar
  106. 106.
    Han SK, Gottsch ML, Lee KJ, Popa SM, Smith JT, Jakawich SK, Clifton DK, Steiner RA, Herbison AE (2005) Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci 25:11349–11356PubMedCrossRefGoogle Scholar
  107. 107.
    Navarro VM, Ruiz-Pino F, Sanchez-Garrido MA, Garcia-Galiano D, Hobbs SJ, Manfredi-­Lozano M, Leon S, Sangiao-Alvarellos S, Castellano JM, Clifton DK, Pinilla L, Steiner RA, Tena-Sempere M (2012) Role of neurokinin B in the control of female puberty and its modulation by metabolic status. J Neurosci 32:2388–2397PubMedCrossRefGoogle Scholar
  108. 108.
    Bentsen AH, Ansel L, Simonneaux V, Tena-Sempere M, Juul A, Mikkelsen JD (2010) Maturation of kisspeptinergic neurons coincides with puberty onset in male rats. Peptides 31:275–283PubMedCrossRefGoogle Scholar
  109. 109.
    Nestor CC, Briscoe AM, Davis SM, Valent M, Goodman RL, Hileman SM (2012) Evidence of a role for kisspeptin and neurokinin B in puberty of female sheep. Endocrinology 153:2756–2765PubMedCrossRefGoogle Scholar
  110. 110.
    Mong JA, Glaser E, McCarthy MM (1999) Gonadal steroids promote glial differentiation and alter neuronal morphology in the developing hypothalamus in a regionally specific manner. J Neurosci 19:1464–1472PubMedGoogle Scholar
  111. 111.
    Mong JA, McCarthy MM (2002) Ontogeny of sexually dimorphic astrocytes in the neonatal rat arcuate. Brain Res Dev Brain Res 139:151–158PubMedCrossRefGoogle Scholar
  112. 112.
    Mong JA, Roberts RC, Kelly JJ, McCarthy MM (2001) Gonadal steroids reduce the density of axospinous synapses in the developing rat arcuate nucleus: an electron microscopy analysis. J Comp Neurol 432:259–267PubMedCrossRefGoogle Scholar
  113. 113.
    Ciofi P, Leroy D, Tramu G (2006) Sexual dimorphism in the organization of the rat hypothalamic infundibular area. Neuroscience 141:1731–1745PubMedCrossRefGoogle Scholar
  114. 114.
    Mong JA, Kurzweil RL, Davis AM, Rocca MS, McCarthy MM (1996) Evidence for sexual differentiation of glia in rat brain. Horm Behav 30:553–562PubMedCrossRefGoogle Scholar
  115. 115.
    Nurhidayat, Tsukamoto Y, Sasaki F (2001) Role of the gonads in sex differentiation of growth hormone-releasing hormone and somatostatin neurons in the mouse hypothalamus during postnatal development. Brain Res 890:154–161PubMedCrossRefGoogle Scholar
  116. 116.
    Losa SM, Todd KL, Sullivan AW, Cao J, Mickens JA, Patisaul HB (2011) Neonatal exposure to genistein adversely impacts the ontogeny of hypothalamic kisspeptin signaling pathways and ovarian development in the peripubertal female rat. Reprod Toxicol 31:280–289PubMedCrossRefGoogle Scholar
  117. 117.
    Castellano JM, Bentsen AH, Mikkelsen JD, Tena-Sempere M (2010) Kisspeptins: bridging energy homeostasis and reproduction. Brain Res 1364:129–138PubMedCrossRefGoogle Scholar
  118. 118.
    Kauffman AS, Clifton DK, Steiner RA (2007) Emerging ideas about kisspeptin- GPR54 signaling in the neuroendocrine regulation of reproduction. Trends Neurosci 30:504–511PubMedCrossRefGoogle Scholar
  119. 119.
    Dungan HM, Clifton DK, Steiner RA (2006) Minireview: kisspeptin neurons as central processors in the regulation of gonadotropin-releasing hormone secretion. Endocrinology 147:1154–1158PubMedCrossRefGoogle Scholar
  120. 120.
    Iijima N, Takumi K, Sawai N, Ozawa H (2011) An immunohistochemical study on the expressional dynamics of kisspeptin neurons relevant to GnRH neurons using a newly developed anti-kisspeptin antibody. J Mol Neurosci 43:146–154PubMedCrossRefGoogle Scholar
  121. 121.
    Caraty A, Fabre-Nys C, Delaleu B, Locatelli A, Bruneau G, Karsch FJ, Herbison A (1998) Evidence that the mediobasal hypothalamus is the primary site of action of estradiol in inducing the preovulatory gonadotropin releasing hormone surge in the ewe. Endocrinology 139:1752–1760PubMedCrossRefGoogle Scholar
  122. 122.
    Hess DL, Wilkins RH, Moossy J, Chang JL, Plant TM, McCormack JT, Nakai Y, Knobil E (1977) Estrogen-induced gonadotropin surges in decerebrated female rhesus monkeys with medial basal hypothalamic peninsulae. Endocrinology 101:1264–1271PubMedCrossRefGoogle Scholar
  123. 123.
    Krey LC, Butler WR, Knobil E (1975) Surgical disconnection of the medial basal hypothalamus and pituitary function in the rhesus monkey. I. Gonadotropin secretion. Endocrinology 96:1073–1087PubMedCrossRefGoogle Scholar
  124. 124.
    Foster DL, Jackson LM, Padmanabhan V (2006) Programming of GnRH feedback controls timing puberty and adult reproductive activity. Mol Cell Endocrinol 254–255:109–119PubMedCrossRefGoogle Scholar
  125. 125.
    Hrabovszky E, Ciofi P, Vida B, Horvath MC, Keller E, Caraty A, Bloom SR, Ghatei MA, Dhillo WS, Liposits Z, Kallo I (2010) The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin-releasing hormone and neurokinin B neurons. Eur J Neurosci 31:1984–1998PubMedCrossRefGoogle Scholar
  126. 126.
    Kauffman AS (2010) Gonadal and nongonadal regulation of sex differences in hypothalamic Kiss1 neurones. J Neuroendocrinol 22:682–691PubMedGoogle Scholar
  127. 127.
    Rance NE (2009) Menopause and the human hypothalamus: evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback. Peptides 30:111–122PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2013

Authors and Affiliations

  • Sheila J. Semaan
    • 1
  • Kristen P. Tolson
    • 1
  • Alexander S. Kauffman
    • 1
  1. 1.Department of Reproductive MedicineUniversity of California, San DiegoLa JollaUSA

Personalised recommendations