Advertisement

Relaxin-Family Peptide and Receptor Systems in Brain: Insights from Recent Anatomical and Functional Studies

  • Sherie Ma
  • Andrew L. Gundlach
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 612)

Abstract

Relaxin was for many years considered primarily a hormone active within the reproductive tract with overwhelming evidence for its important roles in mammalian parturition. More recent research, however, has clearly indicated additional physiological and/or therapeutic roles for relaxin in the cardiovascular, renal and respiratory systems (see other Chapters); while a few studies have also described possible physiological effects of relaxin in the central nervous system, perhaps unsurprisingly associated with the regulation of osmotic homeostasis, blood pressure and neurohormone secretion during pregnancy and parturition. Research on relaxin and subsequently discovered, related peptides has also been particularly productive in the last five years, with some milestone discoveries (see elsewhere in this volume), including the long-awaited identification of the native receptors for relaxin and a related peptide, INSL3—the leucine-rich repeat-containing G-protein-coupled receptors-7 and -8 (LGR7/8); and the identification of a new relaxin family peptide, known as relaxin 3 and its type IG-protein-coupled receptor—GPCR135. Relaxin 3 was subsequently found to be highly conserved throughout evolution and to be the likely ancestral gene/peptide that gave rise to the current relaxin family of genes and peptides in mammals including higher primates. Interestingly, relaxin 3 and its receptor are found in highest abundance in brain, suggesting important central functions for relaxin 3/GPCR135 signaling. In this Chapter we will primarily review what is currently known about the central distribution of relaxin family peptides and their receptors and what has been described so far regarding their effects in the brain. Lastly, we will discuss likely future directions in this interesting, expanding field of research.

Keywords

Theta Rhythm Anterior Olfactory Nucleus Nucleus Incertus Human Relaxin Relaxin Receptor 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Hisaw FL. Experimental relaxation of the pubic ligament of the guinea pig. Proc Soc Exp Biol Med 1926; 23:661–663.Google Scholar
  2. 2.
    Adham IM, Agoulnik AI. Insulin-like 3 signalling in testicular descent. Int J Androl 2004; 27:257–265.PubMedGoogle Scholar
  3. 3.
    Chassin D, Laurent A, Janneau JL et al. Cloning of a new member of the insulin gene superfamily (INSL4) expressed in human placenta. Genomics 1995; 29:465–470.PubMedGoogle Scholar
  4. 4.
    Conklin D, Lofton-Day CE, Haldeman BA et al. Identification of INSL5, a new member of the insulin superfamily. Genomics 1999; 60:50–56.PubMedGoogle Scholar
  5. 5.
    Hsu SY. Cloning of two novel mammalian paralogs of relaxin/insulin family proteins and their expression in testis and kidney. Mol Endocrinol 1999; 13:2163–2174.PubMedGoogle Scholar
  6. 6.
    Lok S, Johnston DS, Conklin D et al. Identification of INSL6, a new member of the insulin family that is expressed in the testis of the human and rat. Biol Reprod 2000; 62:1593–1599.PubMedGoogle Scholar
  7. 7.
    Kasik J, Muglia L, Stephan DA et al. Identification, chromosomal mapping and partial characterization of mouse Insl6: A new member of the insulin family. Endocrinology 2000; 141:458–461.PubMedGoogle Scholar
  8. 8.
    Bathgate RAD, Samuel CS, Burazin TCD et al. Human relaxin gene 3 (H3) and the equivalent mouse relaxin (M3) gene. Novel members of the relaxin peptide family. J Biol Chem 2002; 277:1148–1157.PubMedGoogle Scholar
  9. 9.
    Bathgate RAD, Hsueh AJ, Sherwood OD. Physiology and molecular biology of the relaxin peptide family. In: Neill JD, ed. Knobil and Neill’s Physiology of Reproduction. New York: Academic Press, 2006:701–790.Google Scholar
  10. 10.
    Wilkinson TN, Speed TP, Tregear GW et al. Evolution of the relaxin-like peptide family. BMC Evol Biol 2005;5:14.PubMedGoogle Scholar
  11. 11.
    Adham IM, Burkhardt E, Benahmed M et al. Cloning of a cDNA for a novel insulin-like peptide of the testicular Leydig cells. J Biol Chem 1993; 268:26668–26672.PubMedGoogle Scholar
  12. 12.
    Pusch W, Balvcrs M, Ivell R. Molecular cloning and expression of the relaxin-like factor from the mouse testis. Endocrinology 1996; 137:3009–3013.PubMedGoogle Scholar
  13. 13.
    Burkhardt E, Adham IM, Brosig B et al. Structural organization of the porcine and human genes coding for a Leydig cell-specific insulin-like peptide (LEY I-L) and chromosomal localization of the human gene (INSL3). Genomics 1994; 20:13–19.PubMedGoogle Scholar
  14. 14.
    Koskimies P, Spiess AN, Lahti P et al. The mouse relaxin-like factor gene and its promoter are located within the 3′ region of the JAK3 genomic sequence. FEBS Lett 1997; 419:186–190.PubMedGoogle Scholar
  15. 15.
    Zimmermann S, Schottler P, Engel W et al. Mouse Leydig insulin-like (Ley I-L) gene: Structure and expression during testis and ovary development. Mol Reprod Dev 1997; 47:30–38.PubMedGoogle Scholar
  16. 16.
    Spiess AN, Balvers M, Tena-Sempere M et al. Structure and expression of the rat relaxin-like factor (RLF) gene. Mol Reprod Dev 1999; 54:319–325.PubMedGoogle Scholar
  17. 17.
    Bullesbach EE, Gowan LK, Schwabe C et al. Isolation, purification and the sequence of relaxin from spiny dogfish (Squalus acanthias). Eur J Biochem 1986; 161:335–341.PubMedGoogle Scholar
  18. 18.
    Lu C, Walker WH, Sun J et al. Insulin-like peptide 6: Characterization of secretory status and posttranslational modifications. Endocrinology 2006; 147:5611–5623.PubMedGoogle Scholar
  19. 19.
    Liu C, Kuei C, Sutton S et al. INSL5 is a high affinity specific agonist for GPCR142 (GPR100). J Biol Chem 2005; 280:292–300.PubMedGoogle Scholar
  20. 20.
    Dun SL, Brailoiu E, Wang Y et al. Insulin-like peptide 5: Expression in the mouse brain and mobilization of calcium. Endocrinology 2006; 147:3243–3248.PubMedGoogle Scholar
  21. 21.
    Burazin TCD, Bathgate RAD, Macris M et al. Restricted, but abundant, expression of the novel rat gene-3 (R3) relaxin in the dorsal tegmental region of brain. J Neurochem 2002; 82:1553–1557.PubMedGoogle Scholar
  22. 22.
    Liu C, Eriste E, Sutton S et al. Identification of relaxin-3/INSL7 as an endogenous ligand for the orphan G-protein coupled receptor GPCR135. J Biol Chem 2003; 278:50754–50764.PubMedGoogle Scholar
  23. 23.
    Hsu SY. New insights into the evolution of the relaxin-LGR signaling system. Trends Endocrinol Metab 2003; 14:303–309.PubMedGoogle Scholar
  24. 24.
    Hudson P, Haley J, John M et al. Structure of a genomic clone encoding biologically active human relaxin. Nature 1983; 301:628–631.PubMedGoogle Scholar
  25. 25.
    Crawford RJ, Hudson P, Shine J et al. Two human relaxin genes are on chromosome 9. EMBO J 1984; 3:2341–2345.PubMedGoogle Scholar
  26. 26.
    Garibay-Tupas JL, Csiszar K, Fox M et al. Analysis of the 5′-upstream regions of the human relaxin H1 and H2 genes and their chromosomal localization on chromosome 9p24.1 by radiation hybrid and breakpoint mapping. J Mol Endocrinol 1999; 23:355–365.PubMedGoogle Scholar
  27. 27.
    Bathgate RAD, Scott D, Chung SWL et al. Searching the human genome database for novel relaxin-like peptides. Letts Pept Sci 2002; 8:129–132.Google Scholar
  28. 28.
    Fowler KJ, Clouston WM, Fournier RE et al. The relaxin gene is located on chromosome 19 in the mouse. FEBS Lett 1991; 292:183–186.PubMedGoogle Scholar
  29. 29.
    Schwabe C, Bullesbach EE. Relaxin: Structures, functions, promises and nonevolution. FASEB J 1994; 8:1152–1160.PubMedGoogle Scholar
  30. 30.
    Bryant-Greenwood GD, Schwabe C. Human relaxins: Chemistry and biology. Endocr Rev 1994; 15:5–26.PubMedGoogle Scholar
  31. 31.
    Gast MJ. Studies of luteal generation and processing of the high molecular weight relaxin precursor. Ann N Y Acad Sci 1982; 380:111–125.PubMedGoogle Scholar
  32. 32.
    Gast MJ. Characterization of preprorelaxin by tryptic digestion and inhibition of its conversion to prorelaxin by amino acid analogs. J Biol Chem 1983; 258:9001–9004.PubMedGoogle Scholar
  33. 33.
    Hudson P, Haley J, Cronk M et al. Molecular cloning and characterization of cDNA sequences coding for rat relaxin. Nature 1981; 291:127–131.PubMedGoogle Scholar
  34. 34.
    Hsu SY, Nakabayashi K, Nishi S et al. Activation of orphan receptors by the hormone relaxin. Science 2002; 295:671–674.PubMedGoogle Scholar
  35. 35.
    Tregear GW, Ivell R, Bathgate RAD et al. Proceedings of the Third International Conference on Relaxin and Related Peptides. Dordrecht: Kluwer Academic Publishers; 2001.Google Scholar
  36. 36.
    Bartsch O, Bartlick B, Ivell R. Relaxin signalling links tyrosine phosphorylation to phosphodiesterase and adenylyl cyclase activity. Mol Hum Reprod 2001; 7:799–809.PubMedGoogle Scholar
  37. 37.
    Palejwala S, Stein D, Wojtczuk A et al. Demonstration of a relaxin receptor and relaxin-stimulated tyrosine phosphorylation in human lower uterine segment fibroblasts. Endocrinology 1998; 139:1208–1212.PubMedGoogle Scholar
  38. 38.
    Hsu SY, Kudo M, Chen T et al. The three subfamilies of leucine-rich repeat-containing G protein-coupled receptors (LGR): identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol Endocrinol 2000; 14:1257–1271.PubMedGoogle Scholar
  39. 39.
    Sudo S, Kumagai J, Nishi S et al. H3 relaxin is a specific ligand for LGR7 and activates the receptor by interacting with both the ectodomain and the exoloop 2. J Biol Chem 2003; 278:7855–7862.PubMedGoogle Scholar
  40. 40.
    Hsu SY, Nakabayashi K, Nishi S et al. Relaxin signaling in reproductive tissues. Mol Cell Endocrinol 2003; 202:165–170.PubMedGoogle Scholar
  41. 41.
    Bullesbach EE, Schwabe C. LGR8 signal activation by the relaxin-like factor. J Biol Chem 2005; 280:14586–14590.PubMedGoogle Scholar
  42. 42.
    Halls ML, Bathgate RA, Summers RJ. Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP signaling by distinct mechanisms. Mol Pharmacol 2006; 70:214–226.PubMedGoogle Scholar
  43. 43.
    Kumagai J, Hsu SY, Matsumi H et al. INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. J Biol Chem 2002; 277:31283–31286.PubMedGoogle Scholar
  44. 44.
    Kawamura K, Kumagai J, Sudo S et al. Paracrine regulation of mammalian oocyte maturation and male germ cell survival. Proc Natl Acad Sci USA 2004; 101:7323–7328.PubMedGoogle Scholar
  45. 45.
    Anand-Ivell RJ, Relan V, Balvers M et al. Expression of the insulin-like peptide 3 (INSL3) hormone-receptor (LGR8) system in the testis. Biol Reprod 2006; 74:945–953.PubMedGoogle Scholar
  46. 46.
    Zimmermann S, Steding G, Emmen JM et al. Targeted disruption of the Insl3 gene causes bilateral cryptorchidism. Mol Endocrinol 1999; 13:681–691.PubMedGoogle Scholar
  47. 47.
    Feng S, Cortessis VK, Hwang A et al. Mutation analysis of INSL3 and GREAT/LGR8 genes in familial cryptorchidism. Urology 2004; 64:1032–1036.PubMedGoogle Scholar
  48. 48.
    Gorlov IP, Kamat A, Bogatcheva NV et al. Mutations of the GREAT gene cause cryptorchidism. Hum Mol Genet 2002; 11:2309–2318.PubMedGoogle Scholar
  49. 49.
    Shen PJ, Fu P, Phelan KD et al. Restricted expression of LGR8 in intralaminar thalamic nuclei of rat brain suggests a role in sensorimotor systems. Ann N Y Acad Sci 2005; 1041:510–515.PubMedGoogle Scholar
  50. 50.
    Sedaghat K, Shen P-J, Allbutt H et al. Localization, lesion and functional studies of the INSL3 receptor, LGR8, in brain: Further evidence for role in sensorimotor pathways. Soc Neurosci Abstr 2005: P725.711.Google Scholar
  51. 51.
    Sedaghat K, Shen P-J, Bathgate RAD et al. Leucine-rich repeat-containing G-protein-coupled receptor 8 (LGR8) in rat sensorimotor-basal ganglia circuitry. Soc Neurosci Abstr 2006:P450.24.Google Scholar
  52. 52.
    Liu C, Chen J, Sutton S et al. Identification of relaxin-3/INSL7 as a ligand for GPCR142. J Biol Chem 2003; 278:50765–50770.PubMedGoogle Scholar
  53. 53.
    Matsumoto M, Kamohara M, Sugimoto T et al. The novel G-protein coupled receptor SALPR shares sequence similarity with somatostatin and angiotensin receptors. Gene 2000; 248:183–189.PubMedGoogle Scholar
  54. 54.
    Sutton SW, Bonaventure P, Kuei C et al. G-protein-coupled receptor (GPCR)-142 does not contribute to relaxin-3 binding in the mouse brain: Further support that relaxin-3 is the physiological ligand for GPCR135. Neuroendocrinology 2006; 82:139–150.PubMedGoogle Scholar
  55. 55.
    Liu C, Chen J, Kuei C et al. Relaxin-3/insulin-like peptide 5 chimeric peptide, a selective ligand for G protein-coupled receptor (GPCR)135 and GPCR142 over leucine-rich repeat-containing G protein-coupled receptor 7. Mol Pharmacol 2005; 67:231–240.PubMedGoogle Scholar
  56. 56.
    Sherwood OD. Relaxin’s physiological roles and other diverse actions. Endocr Rev 2004; 25:205–234.PubMedGoogle Scholar
  57. 57.
    Gunnersen JM, Crawford RJ, Tregear GW. Expression of the relaxin gene in rat tissues. Mol Cell Endocrinol 1995; 110:55–64.PubMedGoogle Scholar
  58. 58.
    Samuel CS, Tian H, Zhao L et al. Relaxin is a key mediator of prostate growth and male reproductive tract development. Lab Invest 2003; 83:1055–1067.PubMedGoogle Scholar
  59. 59.
    Ivell R, Hartung S. The molecular basis of cryptorchidism. Mol Hum Reprod 2003; 9:175–181.PubMedGoogle Scholar
  60. 60.
    Ferlin A, Simonato M, Bartoloni L et al. The INSL3-LGR8/GREAT ligand-receptor pair in human cryptorchidism. J Clin Endocrinol Metab 2003; 88:4273–4279.PubMedGoogle Scholar
  61. 61.
    Roh J, Virtanen H, Kumagai J et al. Lack of LGR8 gene mutation in Finnish patients with a family history of cryptorchidism. Reprod Biomed Online 2003; 7:400–406.PubMedGoogle Scholar
  62. 62.
    Ferlin A, Bogatcheva NV, Gianesello L et al. Insulin-like factor 3 gene mutations in testicular dysgenesis syndrome: Clinical and functional characterization. Mol Hum Reprod 2006; 12:401–406.PubMedGoogle Scholar
  63. 63.
    OsherofF PL, Ho W-H. Expression of relaxin mRNA and relaxin receptors in postnatal and adult rat brains and hearts. J Biol Chem 1993; 268:15193–15199.PubMedGoogle Scholar
  64. 64.
    Burazin TCD, Davern P, McKinley MJ et al. Identification of relaxin and relaxin responsive cells in the rat brain. In: Tregear GW, Ivell R, Bathgate RAD, Wade JD, ed. Proceedings of the Third International Conference on Relaxin and Related Peptides. Dordrecht: Kluwer Academic Publishers, 2001:209–214.Google Scholar
  65. 65.
    Ma S, Roozendaal B, Burazin TCD et al. Relaxin receptor activation in the basolateral amygdala impairs memory consolidation. Eur J Neurosci 2005; 22:2117–2122.PubMedGoogle Scholar
  66. 66.
    Allen Institute for Brain Science. Allen Brain Atlas [Website]. Available at: http://www.brain-map.org. Accessed October, 2006.
  67. 67.
    Hokfelt T, Broberger C, Xu ZQ. et al. Neuropeptides—an overview. Neuropharmacology 2000; 39:1337–1356.PubMedGoogle Scholar
  68. 68.
    Ludwig M, Leng G. Dendritic peptide release and peptide-dependent behaviours. Nat Rev Neurosci 2006; 7:126–136.PubMedGoogle Scholar
  69. 69.
    Tanaka M, Iijima N, Miyamoto Y et al. Neurons expressing relaxin 3/INSL 7 in the nucleus incertus respond to stress. Eur J Neurosci 2005; 21:1659–1670.PubMedGoogle Scholar
  70. 70.
    Ma S, Bonavcnturc P, Ferraro T et al. Relaxin-3 in GABA projection neurons of nucleus incertus suggests widespread influence on forebrain circuits via G-protein-coupled receptor-135 in the rat. Neuroscience 2007;144:165–190.PubMedGoogle Scholar
  71. 71.
    Papez J. Comparative Neurology. New York, 1929.Google Scholar
  72. 72.
    Chatfield PO, Lyman CP. An unusual structure in the floor of the fourth ventricle of the golden hamster, Mesocricetus auratus. J Comp Neurol 1954;101:225–235.PubMedGoogle Scholar
  73. 73.
    Meesen H, Olszewski J. A Cytoarchitectonic Adas of the Rhombencephalon of the Rabbit. Basel, 1949.Google Scholar
  74. 74.
    Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. New York: Academic Press, 1986.Google Scholar
  75. 75.
    Jennes L, Stumpf WE, Kalivas PW. Neurotensin: Topographical distribution in rat brain by immunohistochemistry. J Comp Neurol 1982;210:211–224.PubMedGoogle Scholar
  76. 76.
    Morest DK. Connexions of the dorsal tegmental nucleus in rat and rabbit. J Anat 1961;95:229–246.PubMedGoogle Scholar
  77. 77.
    Bittencourt JC, Sawchenko PE. Do centrally administered neuropeptides access cognate receptors? An analysis in the central corticotropin-releasing factor system. J Neurosci 2000;20:1142–1156.PubMedGoogle Scholar
  78. 78.
    Goto M, Swanson LW, Cameras NS. Connections of the nucleus incertus. J Comp Neurol 2001;438:86–122.PubMedGoogle Scholar
  79. 79.
    Olucha-Bordonau FE, Teruel V, Barcia-Gonzalez J et al. Cytoarchitecture and efferent projections of the nucleus incertus of the rat. J Comp Neurol 2003;464:62–97.PubMedGoogle Scholar
  80. 80.
    Bathgate RAD, Ivell R, Sanborn BM et al. International Union of Pharmacology LVII: Recommendations for the nomenclature of receptors for relaxin family peptides. Pharmacol Rev 2006;58:7–31.PubMedGoogle Scholar
  81. 81.
    Osheroff PL, Phillips HS. Autoradiographic localization of relaxin binding sites in rat brain. Proc Natl Acad Sci USA 1991;88:6413–6417.PubMedGoogle Scholar
  82. 82.
    Ma S, Shen PJ, Burazin TCD et al. Comparative localization of leucine-rich repeat-containing G-protein-coupled receptor-7 (RXFP1) mRNA and [(33)P]-relaxin binding sites in rat brain: Restricted somatic coexpression a clue to relaxin action? Neuroscience 2006;141:329–344.PubMedGoogle Scholar
  83. 83.
    Sutton SW, Bonaventure P, Kuei C et al. Distribution of G-protein-coupled receptor (GPCR)135 binding sites and receptor mRNA in the rat brain suggests a role for relaxin-3 in neuroendocrine and sensory processing. Neuroendocrinology 2004;80:298–307.PubMedGoogle Scholar
  84. 84.
    Krajnc-Franken MA, Van Disseldorp AJ, Koenders JE et al. Impaired nipple development and parturition in LGR7 knockout mice. Mol Cell Biol 2004;24:687–696.PubMedGoogle Scholar
  85. 85.
    Piccenna L, Shen P-J, Ma S et al. Localization of LGR7 gene expression in adult mouse brain using LGR7 knock-out/LacZ knock-in mice: Correlation with LGR7 mRNA distribution. Ann N Y Acad Sci 2005;1041:197–204.PubMedGoogle Scholar
  86. 86.
    Sinnayah P, Burns P, Wade JD et al. Water drinking in rats resulting from intravenous relaxin and its modification by other dipsogenic factors. Endocrinology 1999;140:5082–5086.PubMedGoogle Scholar
  87. 87.
    Summerlee AJ, Hornsby DJ, Ramsey DG. The dipsogenic effects of rat relaxin: The effect of photoperiod and the potential role of relaxin on drinking in pregnancy. Endocrinology 1998;139:2322–2328.PubMedGoogle Scholar
  88. 88.
    Gross PM. Circumventricular organ capillaries. Prog Brain Res 1992;91:219–233.PubMedGoogle Scholar
  89. 89.
    Sunn N, McKinley MJ, Oldfield BJ. Identification of efferent neural pathways from the lamina terminalis activated by blood-borne relaxin. J Neuroendocrinol 2001;13:432–437.PubMedGoogle Scholar
  90. 90.
    Bathgate RAD, Lin F, Hanson NF et al. Relaxin-3: Improved synthesis strategy and demonstration of its high-affinity interaction with the relaxin receptor LGR7 both in vitro and in vivo. Biochemistry 2006;45:1043–1053.PubMedGoogle Scholar
  91. 91.
    Thornton SM, Fitzsimons JT. The effects of centrally administered porcine relaxin on drinking behaviour in male and female rats. J Neuroendocrinol 1995;7:165–169.PubMedGoogle Scholar
  92. 92.
    O’Byrne KT, Eltringham L, Summerlee AJ. Central inhibitory effects of relaxin on the milk ejection reflex of the rat depends upon the site of injection into the cerebroventricular system. Brain Res 1987;405:80–83.PubMedGoogle Scholar
  93. 93.
    Parry LJ, Poterski RS, Summerlee AJ. Effects of relaxin on blood pressure and the release of vasopressin and oxytocin in anesthetized rats during pregnancy and lactation. Biol Reprod 1994;50:622–628.PubMedGoogle Scholar
  94. 94.
    Heine PA, Di S, Ross LR anderson LL et al. Relaxin-induced expression of Fos in the forebrain of the late pregnant rat. Neuroendocrinology 1997;66:38–46.PubMedGoogle Scholar
  95. 95.
    McKinley MJ, Burns P, Colvill LM et al. Distribution of Fos immunoreactivity in the lamina terminalis and hypothalamus induced by centrally administered relaxin in conscious rats. J Neuroendocrinol 1997;9:431–437.PubMedGoogle Scholar
  96. 96.
    Cronin MJ, Malaska T. Characterization of relaxin-stimulated cyclic AMP in cultured rat anterior pituitary cells: Influence of dopamine, somatostatin and gender. J Mol Endocrinol 1989;3:175–182.PubMedGoogle Scholar
  97. 97.
    McGowan BM, Stanley SA, Smith KL et al. Central relaxin-3 administration causes hyperphagia in male Wistar rats. Endocrinology 2005;146:3295–3300.PubMedGoogle Scholar
  98. 98.
    McGowan BM, Stanley SA, Smith KL et al. Effects of acute and chronic relaxin-3 on food intake and energy expenditure in rats. Regul Pept 2006;136:72–77.PubMedGoogle Scholar
  99. 99.
    Hida T, Takahashi E, Shikata K et al. Chronic intracerebroventricular administration of rclaxin-3 increases body weight in rats. J Recept Signal Transduct Res 2006;26:147–158.PubMedGoogle Scholar
  100. 100.
    Hwang JJ, Sherwood OD. Monoclonal antibodies specific for rat relaxin. III. Passive immunization with monoclonal antibodies throughout the second half of pregnancy reduces cervical growth and extensibility in intact rats. Endocrinology 1988;123:2486–2490.PubMedGoogle Scholar
  101. 101.
    Guico-Lamm ML, Sherwood OD. Monoclonal antibodies specific for rat relaxin. II. Passive immunization with monoclonal antibodies throughout the second half of pregnancy disrupts birth in intact rats. Endocrinology 1988;123:2479–2485.PubMedGoogle Scholar
  102. 102.
    Kuenzi MJ, Sherwood OD. Monoclonal antibodies specific for rat relaxin. VII. Passive immunization with monoclonal antibodies throughout the second half of pregnancy prevents development of normal mammary nipple morphology and function in rats. Endocrinology 1992;131:1841–1847.PubMedGoogle Scholar
  103. 103.
    Summerlee AJ, Ramsey DG, Poterski RS. Neutralization of relaxin within the brain affects the timing of birth in rats. Endocrinology 1998;139:479–484.PubMedGoogle Scholar
  104. 104.
    Zhao L, Roche PJ, Gunnersen JM et al. Mice without a functional relaxin gene are unable to deliver milk to their pups. Endocrinology 1999;140:445–453.PubMedGoogle Scholar
  105. 105.
    Price JL. Comparative aspects of amygdala connectivity. Ann N Y Acad Sci 2003;985:50–58.PubMedGoogle Scholar
  106. 106.
    Sah P, Faber ES, Lopez De Armentia M et al. The amygdaloid complex: Anatomy and physiology. Physiol Rev 2003;83:803–834.PubMedGoogle Scholar
  107. 107.
    Pitkanen A. Connectivity of the rat amygdaloid complex. In: Aggleton JP, ed. The Amygdala: A Functional Analysis. Oxford, UK: Oxford University Press, 2000:31–115.Google Scholar
  108. 108.
    Cardinal RN, Parkinson JA, Hall J et al. Emotion and motivation: The role of the amygdala, ventral striatum and prefrontal cortex. Neurosci Biobehav Rev 2002;26:321–352.PubMedGoogle Scholar
  109. 109.
    Hamann SB, Ely TD, Grafton ST et al. Amygdala activity related to enhanced memory for pleasant and aversive stimuli. Nat Neurosci 1999;2:289–293.PubMedGoogle Scholar
  110. 110.
    McGaugh JL, McIntyre CK, Power AE. Amygdala modulation of memory consolidation: Interaction with other brain systems. Neurobiol Learn Mem 2002;78:539–552.PubMedGoogle Scholar
  111. 111.
    McGaugh JL. The amygdala modulates the consolidation of memories of emotionally arousing experiences. Annu Rev Neurosci 2004;27:1–28.PubMedGoogle Scholar
  112. 112.
    Nunez A, Cervera-Ferri A, Olucha-Bordonau F et al. Nucleus incertus contribution to hippocampal theta rhythm generation. Eur J Neurosci 2006;23:2731–2738.PubMedGoogle Scholar
  113. 113.
    Banerjee A, Ma S, Ortinau S et al. Relaxin-3 neurons in the nucleus incertus: Projection patterns, response to swim stress and RLX3 neuronal signaling. Soc Neurosci Abstr 2005;35:59.57.Google Scholar
  114. 114.
    Hamann S. Nosing in on the emotional brain. Nat Neurosci 2003;6:106–108.PubMedGoogle Scholar
  115. 115.
    Schoenbaum G, Chiba AA, Gallagher M. Neural encoding in orbitofrontal cortex and basolateral amygdala during olfactory discrimination learning. J Neurosci 1999;19:1876–1884.PubMedGoogle Scholar
  116. 116.
    Dielenberg RA, McGregor IS. Defensive behavior in rats towards predatory odors: A review. Neurosci Biobehav Rev 2001;25:597–609.PubMedGoogle Scholar
  117. 117.
    Levy F, Keller M, Poindron P. Olfactory regulation of maternal behavior in mammals. Horm Behav 2004;46:284–302.PubMedGoogle Scholar
  118. 118.
    Crawley JN. Behavioral phenotyping of transgenic and knockout mice: Experimental design and evaluation of general health, sensory functions, motor abilities and specific behavioral tests. Brain Res 1999;835:18–26.PubMedGoogle Scholar
  119. 119.
    Silvertown JD, Geddes BJ, Summerlee AJ. Adenovirus-mediated expression of human prorelaxin promotes the invasive potential of canine mammary cancer cells. Endocrinology 2003;144:3683–3691.PubMedGoogle Scholar
  120. 120.
    Bell GI, Pictet RL, Rutter WJ et al. Sequence of the human insulin gene. Nature 1980;284:26–32.PubMedGoogle Scholar
  121. 121.
    Jansen M, van Schaik FM, Ricker AT et al. Sequence of cDNA encoding human insulin-like growth factor I precursor. Nature 1983;306:609–611.PubMedGoogle Scholar
  122. 122.
    Bell GI, Merryweather JP, Sanchez-Pescador R et al. Sequence of a cDNA clone encoding human preproinsulin-like growth factor II. Nature 1984;310:775–777.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  1. 1.Howard Florey InstituteThe University of MelbourneVictoriaAustralia

Personalised recommendations