Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

A remote and highly conserved enhancer supports amygdala specific expression of the gene encoding the anxiogenic neuropeptide substance-P

Molecular Psychiatry volume 11, pages 410–421 (2006)Cite this article

Abstract

The neuropeptide substance P (SP), encoded by the preprotachykinin-A (PPTA) gene, is expressed in the central and medial amygdaloid nucleus, where it plays a critical role in modulating fear and anxiety related behaviour. Determining the regulatory systems that support PPTA expression in the amygdala may provide important insights into the causes of depression and anxiety related disorders and will provide avenues for the development of novel therapies. In order to identify the tissue specific regulatory element responsible for supporting expression of the PPTA gene in the amygdala, we used long-range comparative genomics in combination with transgenic analysis and immunohistochemistry. By comparing human and chicken genomes, it was possible to detect and characterise a highly conserved long-range enhancer that supported tissue specific expression in SP expressing cells of the medial and central amygdaloid bodies (ECR1; 158.5 kb 5′ of human PPTA ORF). Further bioinformatic analysis using the TRANSFAC database indicated that the ECR1 element contained multiple and highly conserved consensus binding sequences of transcription factors (TFs) such as MEIS1. The results of immunohistochemical analysis of transgenic lines were consistent with the hypothesis that the MEIS1 TF interacts with and maintains ECR1 activity in the central amygdala in vivo. The discovery of ECR1 and the in vivo functional relationship with MEIS1 inferred by our studies suggests a mechanism to the regulatory systems that control PPTA expression in the amygdala. Uncovering these mechanisms may play an important role in the future development of tissue specific therapies for the treatment of anxiety and depression.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Golden RN . Making advances where it matters: improving outcomes in mood and anxiety disorders. CNS Spectrosc 2004; 9 (6 Suppl 4): 14–22.

    Article  Google Scholar 

  2. Huezo-Diaz P, Tandon K, Aitchison KJ . The genetics of depression and related traits. Curr Psychiatry Rep 2005; 7: 117–124.

    Article  PubMed  Google Scholar 

  3. Coplan JD, Lydiard RB . Brain circuits in panic disorder. Biol Psychiatry 1998; 44: 1264–1276.

    Article  CAS  PubMed  Google Scholar 

  4. Misslin R . The defense system of fear: behavior and neurocircuitry. Neurophysiol Clin 2003; 33: 55–66.

    Article  PubMed  Google Scholar 

  5. Sajdyk TJ, Shekhar A, Gehlert DR . Interactions between NPY and CRF in the amygdala to regulate emotionality. Neuropeptides 2004; 38: 225–234.

    Article  CAS  PubMed  Google Scholar 

  6. Watanabe T, Nakagawa T, Yamamoto R, Maeda A, Minami M, Satoh M . Involvement of glutamate receptors within the central nucleus of the amygdala in naloxone-precipitated morphine withdrawal-induced conditioned place aversion in rats. Jpn J Pharmacol 2002; 88: 399–406.

    Article  CAS  PubMed  Google Scholar 

  7. McBride WJ . Central nucleus of the amygdala and the effects of alcohol and alcohol-drinking behavior in rodents. Pharmacol Biochem Behav 2002; 71: 509–515.

    Article  CAS  PubMed  Google Scholar 

  8. Neugebauer V, Li W, Bird GC, Han JS . The amygdala and persistent pain. Neuroscientist 2004; 10: 221–234.

    Article  PubMed  Google Scholar 

  9. Takahashi LK, Nakashima BR, Hong H, Watanabe K . The smell of danger: a behavioral and neural analysis of predator odor-induced fear. Neurosci Biobehav Rev 2005; 29: 1157–1167.

    Article  PubMed  Google Scholar 

  10. Carrasco GA, Van de Kar LD . Neuroendocrine pharmacology of stress. Eur J Pharmacol 2003; 463: 235–272.

    Article  CAS  PubMed  Google Scholar 

  11. MacKenzie A, Quinn JP . Post-genomic approaches to exploring neuropeptide gene mis-expression in disease. Neuropeptides 2004; 38: 1–15.

    Article  CAS  PubMed  Google Scholar 

  12. Adell A . Antidepressant properties of substance P antagonists: relationship to monoaminergic mechanisms? Curr Drug Targets CNS Neurol Disord 2004; 3: 113–121.

    Article  CAS  PubMed  Google Scholar 

  13. Bosker FJ, Westerink BH, Cremers TI, Gerrits M, van der Hart MG, Kuipers SD et al. Future antidepressants: what is in the pipeline and what is missing? CNS Drugs 2004; 18: 705–732.

    Article  CAS  PubMed  Google Scholar 

  14. Herpfer I, Lieb K . Substance P receptor antagonists in psychiatry: rationale for development and therapeutic potential. CNS Drugs 2005; 19: 275–293.

    Article  CAS  PubMed  Google Scholar 

  15. Pennefather JN, Lecci A, Candenas ML, Patak E, Pinto FM, Maggi CA . Tachykinins and tachykinin receptors: a growing family. Life Sci 2004; 74: 1445–1463.

    Article  CAS  PubMed  Google Scholar 

  16. Maggi CA . The mammalian tachykinin receptors. Gen Pharmacol 1995; 26: 911–944.

    Article  CAS  PubMed  Google Scholar 

  17. De Felipe C, Herrero JF, O'Brien JA, Palmer JA, Doyle CA, Smith AJ et al. Altered nociception, analgesia and aggression in mice lacking the receptor for substance P. Nature 1998; 392: 394–397.

    Article  CAS  PubMed  Google Scholar 

  18. Bilkei-Gorzo A, Racz I, Michel K, Zimmer A . Diminished anxiety- and depression-related behaviors in mice with selective deletion of the Tac1 gene. J Neurosci 2002; 22: 10046–10052.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ribeiro-da-Silva A, Hokfelt T . Neuroanatomical localisation of Substance P in the CNS and sensory neurons. Neuropeptides 2000; 34: 256–271.

    Article  CAS  PubMed  Google Scholar 

  20. Yao R, Rameshwar P, Donnelly RJ, Siegel A . Neurokinin-1 expression and co-localization with glutamate and GABA in the hypothalamus of the cat. Brain Res Mol Brain Res 1999; 71: 149–158.

    Article  CAS  PubMed  Google Scholar 

  21. Sergeyev V, Fetissov S, Mathe AA, Jimenez PA, Bartfai T, Mortas P et al. Neuropeptide expression in rats exposed to chronic mild stresses. Psychopharmacology (Berl) 2005; 178: 115–124.

    Article  CAS  Google Scholar 

  22. Ebner K, Rupniak NM, Saria A, Singewald N . Substance P in the medial amygdala: emotional stress-sensitive release and modulation of anxiety-related behavior in rats. Proc Natl Acad Sci USA 2004; 101: 4280–4285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ranga K, Krishnan R . Clinical experience with substance P receptor (NK1) antagonists in depression. J Clin Psychiatry 2002; 63 (Suppl 11): 25–29.

    CAS  PubMed  Google Scholar 

  24. Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J, Sramek JJ et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 1998; 281: 1640–1645.

    Article  CAS  PubMed  Google Scholar 

  25. Ogden CA, Rich ME, Schork NJ, Paulus MP, Geyer MA, Lohr JB et al. Candidate genes, pathways and mechanisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach. Mol Psychiatry 2004; 9: 1007–1029.

    Article  CAS  PubMed  Google Scholar 

  26. Gadd CA, Murtra P, De Felipe C, Hunt SP . Neurokinin-1 receptor-expressing neurons in the amygdala modulate morphine reward and anxiety behaviors in the mouse. J Neurosci 2003; 23: 8271–8280.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Quinn JP, Fiskerstrand CE, Gerrard L, MacKenzie A, Payne CM . Molecular models to analyse preprotachykinin-A expression and function. Neuropeptides 2000; 34: 292–302.

    Article  CAS  PubMed  Google Scholar 

  28. Walker PD, Andrade R, Quinn JP, Bannon MJ . Real-time analysis of preprotachykinin promoter activity in single cortical neurons. J Neurochem 2000; 75: 882–885.

    Article  CAS  PubMed  Google Scholar 

  29. Hilton KJ, Bateson AN, King AE . A model of organotypic rat spinal slice culture and biolistic transfection to elucidate factors that drive the preprotachykinin-A promoter. Brain Res Brain Res Rev 2004; 46: 191–203.

    Article  CAS  PubMed  Google Scholar 

  30. Harmar AJ, Mulderry PK, al-Shawi R, Lyons V, Sheward WJ, Bishop JO et al. 3.3 kb of 5′ flanking DNA from the rat preprotachykinin gene directs high level expression of a reporter gene in microinjected dorsal root ganglion neurons but not in transgenic mice. Regul Peptides 1993; 46: 67–69.

    Article  CAS  Google Scholar 

  31. Millward-Sadler SJ, Mackenzie A, Wright MO, Lee HS, Elliot K, Gerrard L et al. Tachykinin expression in cartilage and function in human articular chondrocyte mechanotransduction. Arthritis Rheum 2003; 48: 146–156.

    Article  CAS  PubMed  Google Scholar 

  32. MacKenzie A, Quinn J . A yeast artificial chromosome containing the human preprotachykinin-A gene expresses substance P in mice and drives appropriate marker gene expression during early brain embryogenesis. Mol Cell Neurosci 2002; 19: 72–87.

    Article  CAS  PubMed  Google Scholar 

  33. MacKenzie A, Payne C, Boyle S, Clarke AR, Quinn JP . The human preprotachykinin-A gene promoter has been highly conserved and can drive human-like marker gene expression in the adult mouse CNS. Mol Cell Neurosci 2000; 16: 620–630.

    Article  CAS  PubMed  Google Scholar 

  34. Ovcharenko I, Nobrega MA, Loots GG, Stubbs L . ECR Browser: a tool for visualizing and accessing data from comparisons of multiple vertebrate genomes. Nucleic Acids Res 2004; 32 (Web Server Issue): W280–W286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Matys V, Fricke E, Geffers R, Gossling E, Haubrock M, Hehl R et al. TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res 2003; 31: 374–378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yee SP, Rigby PW . The regulation of myogenin gene expression during the embryonic development of the mouse. Genes Dev 1993; 7: 1277–1289.

    Article  CAS  PubMed  Google Scholar 

  37. MacKenzie A, Purdie L, Davidson D, Collinson M, Hill RE . Two enhancer domains control early aspects of the complex expression pattern of Msx1. Mech Dev 1997; 62: 29–40.

    Article  CAS  PubMed  Google Scholar 

  38. MacKenzie A, Quinn J . A serotonin transporter gene intron 2 polymorphic region, correlated with affective disorders, has allele-dependent differential enhancer- like properties in the mouse embryo. Proc Natl Acad Sci USA 1999; 96: 15251–15255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hogan B, Beddington R, Constantini F, Lacy E . Manipulating the Mouse Embryo. Cold Spring Harbor Laborotory Press: New York, 1995.

    Google Scholar 

  40. Wallis JW, Aerts J, Groenen MA, Crooijmans RP, Layman D, Graves TA et al. A physical map of the chicken genome. Nature 2004; 432: 761–764.

    Article  CAS  PubMed  Google Scholar 

  41. Pevzner P, Tesler G . Genome rearrangements in mammalian evolution: lessons from human and mouse genomes. Genome Res 2003; 13: 37–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mackenzie A, Miller KA, Collinson JM . Is there a functional link between gene interdigitation and multi-species conservation of synteny blocks? Bioessays 2004; 26: 1217–1224.

    Article  CAS  PubMed  Google Scholar 

  43. Fogel GB, Weekes DG, Varga G, Dow ER, Craven AM, Harlow HB et al. A statistical analysis of the TRANSFAC database. Biosystems 2005; 81: 137–154.

    Article  CAS  PubMed  Google Scholar 

  44. Sun P, Loh HH . Transcriptional regulation of mouse delta-opioid receptor gene: role of Ets-1 in the transcriptional activation of mouse delta-opioid receptor gene. J Biol Chem 2001; 276: 45462–45469.

    Article  CAS  PubMed  Google Scholar 

  45. Toresson H, Parmar M, Campbell K . Expression of Meis and Pbx genes and their protein products in the developing telencephalon: implications for regional differentiation. Mech Dev 2000; 94: 183–187.

    Article  CAS  PubMed  Google Scholar 

  46. Spector TD, MacGregor AJ . Risk factors for osteoarthritis: genetics. Osteoarthritis Cartilage 2004; 12 (Suppl A): S39–S44.

    Article  PubMed  Google Scholar 

  47. Blumenthal MN . The role of genetics in the development of asthma and atopy. Curr Opin Allergy Clin Immunol 2005; 5: 141–145.

    Article  CAS  PubMed  Google Scholar 

  48. Brant SR, Shugart YY . Inflammatory bowel disease gene hunting by linkage analysis: rationale, methodology, and present status of the field. Inflamm Bowel Dis 2004; 10: 300–311.

    Article  PubMed  Google Scholar 

  49. Malhi GS, Moore J, McGuffin P . The genetics of major depressive disorder. Curr Psychiatry Rep 2000; 2: 165–169.

    Article  CAS  PubMed  Google Scholar 

  50. Morley M, Molony CM, Weber TM, Devlin JL, Ewens KG, Spielman RS et al. Genetic analysis of genome-wide variation in human gene expression. Nature 2004; 430: 743–747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Pastinen T, Hudson TJ . Cis-acting regulatory variation in the human genome. Science 2004; 306: 647–650.

    Article  CAS  PubMed  Google Scholar 

  52. Wittkopp PJ, Haerum BK, Clark AG . Evolutionary changes in cis and trans gene regulation. Nature 2004; 430: 85–88.

    Article  CAS  PubMed  Google Scholar 

  53. Santini S, Boore JL, Meyer A . Evolutionary conservation of regulatory elements in vertebrate hox gene clusters. Genome Res 2003; 13: 1111–1122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tullai JW, Schaffer ME, Mullenbrock S, Kasif S, Cooper GM . Identification of transcription factor binding sites upstream of human genes regulated by the phosphatidylinositol 3-kinase and MEK/ERK signaling pathways. J Biol Chem 2004; 279: 20167–20177.

    Article  CAS  PubMed  Google Scholar 

  55. Lee SK, Choi YS, Cha J, Moon EJ, Lee SW, Bae MK et al. Identification of novel anti-angiogenic factors by in silico functional gene screening method. J Biotechnol 2003; 105: 51–60.

    Article  CAS  PubMed  Google Scholar 

  56. Honkaniemi J, Kainu T, Ceccatelli S, Rechardt L, Hokfelt T, Pelto-Huikko M . Fos and jun in rat central amygdaloid nucleus and paraventricular nucleus after stress. Neuroreport 1992; 3: 849–852.

    Article  CAS  PubMed  Google Scholar 

  57. Arnold FJ, De Lucas Bueno M, Shiers H, Hancock DC, Evan GI, Herbert J . Expression of c-fos in regions of the basal limbic forebrain following intracerebroventricular corticotropin-releasing factor in unstressed or stressed male rats. Neuroscience 1992; 51: 377–390.

    Article  CAS  PubMed  Google Scholar 

  58. Honkaniemi J, Pelto-Huikko M, Rechardt L, Isola J, Lammi A, Fuxe K et al. Colocalization of peptide and glucocorticoid receptor immunoreactivities in rat central amygdaloid nucleus. Neuroendocrinology 1992; 55: 451–459.

    Article  CAS  PubMed  Google Scholar 

  59. Sterneck E, Johnson PF . CCAAT/enhancer binding protein beta is a neuronal transcriptional regulator activated by nerve growth factor receptor signaling. J Neurochem 1998; 70: 2424–2433.

    Article  CAS  PubMed  Google Scholar 

  60. Moskow JJ, Bullrich F, Huebner K, Daar IO, Buchberg AM . Meis1, a PBX1-related homeobox gene involved in myeloid leukemia in BXH-2 mice. Mol Cell Biol 1995; 15: 5434–5443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Hisa T, Spence SE, Rachel RA, Fujita M, Nakamura T, Ward JM et al. Hematopoietic, angiogenic and eye defects in Meis1 mutant animals. EMBO J 2004; 23: 450–459.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Shen WF, Montgomery JC, Rozenfeld S, Moskow JJ, Lawrence HJ, Buchberg AM et al. AbdB-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins. Mol Cell Biol 1997; 17: 6448–6458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Saleh M, Huang H, Green NC, Featherstone MS . A conformational change in PBX1A is necessary for its nuclear localization. Exp Cell Res 2000; 260: 105–115.

    Article  CAS  PubMed  Google Scholar 

  64. Rieckhof GE, Casares F, Ryoo HD, Abu-Shaar M, Mann RS . Nuclear translocation of extradenticle requires homothorax, which encodes an extradenticle-related homeodomain protein. Cell 1997; 91: 171–183.

    Article  CAS  PubMed  Google Scholar 

  65. Koh MT, Bernstein IL . Inhibition of protein kinase A activity during conditioned taste aversion retrieval: interference with extinction or reconsolidation of a memory? Neuroreport 2003; 14: 405–407.

    Article  CAS  PubMed  Google Scholar 

  66. Goosens KA, Holt W, Maren S . A role for amygdaloid PKA and PKC in the acquisition of long-term conditional fear memories in rats. Behav Brain Res 2000; 114: 145–152.

    Article  CAS  PubMed  Google Scholar 

  67. Adler JE, Walker PD . Cyclic AMP regulates substance P expression in developing and mature spinal sensory neurons. J Neurosci Res 2000; 59: 624–631.

    Article  CAS  PubMed  Google Scholar 

  68. Huang H, Rastegar M, Bodner C, Goh SL, Rambaldi I, Featherstone M . MEIS C termini harbor transcriptional activation domains that respond to cell signaling. J Biol Chem 2005; 280: 10119–10127.

    Article  CAS  PubMed  Google Scholar 

  69. Bischof LJ, Kagawa N, Moskow JJ, Takahashi Y, Iwamatsu A, Buchberg AM et al. Members of the meis1 and pbx homeodomain protein families cooperatively bind a cAMP-responsive sequence (CRS1) from bovine CYP17. J Biol Chem 1998; 273: 7941–7948.

    Article  CAS  PubMed  Google Scholar 

  70. Schmidt EE, Schibler U . Cell size regulation, a mechanism that controls cellular RNA accumulation: consequences on regulation of the ubiquitous transcription factors Oct1 and NF-Y and the liver-enriched transcription factor DBP. J Cell Biol 1995; 128: 467–483.

    Article  CAS  PubMed  Google Scholar 

  71. Cote F, Schussler N, Boularand S, Peirotes A, Thevenot E, Mallet J et al. Involvement of NF-Y and Sp1 in basal and cAMP-stimulated transcriptional activation of the tryptophan hydroxylase (TPH) gene in the pineal gland. J Neurochem 2002; 81: 673–685.

    Article  CAS  PubMed  Google Scholar 

  72. Schwaninger M, Petersen N, Prinz S, Sallmann S, Neher M, Spranger M . Adenosine-induced expression of interleukin-6 in astrocytes through protein kinase A and NF-IL-6. Glia 2000; 31: 51–58.

    Article  CAS  PubMed  Google Scholar 

  73. Yokoyama M, Suzuki E, Sato T, Maruta S, Watanabe S, Miyaoka H . Amygdalic levels of dopamine and serotonin rise upon exposure to conditioned fear stress without elevation of glutamate. Neurosci Lett 2005; 379: 37–41.

    Article  CAS  PubMed  Google Scholar 

  74. Weiner DM, Levey AI, Sunahara RK, Niznik HB, O'Dowd BF, Seeman P et al. D1 and D2 dopamine receptor mRNA in rat brain. Proc Natl Acad Sci USA 1991; 88: 1859–1863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Waddington JL, O'Tuathaigh C, O'Sullivan G, Tomiyama K, Koshikawa N, Croke DT . Phenotypic studies on dopamine receptor subtype and associated signal transduction mutants: insights and challenges from 10 years at the psychopharmacology-molecular biology interface. Psychopharmacology (Berl) 2005; 1–28.

  76. Cornea-Hebert V, Riad M, Wu C, Singh SK, Descarries L . Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol 1999; 409: 187–209.

    Article  CAS  PubMed  Google Scholar 

  77. Duxon MS, Flanigan TP, Reavley AC, Baxter GS, Blackburn TP, Fone KC . Evidence for expression of the 5-hydroxytryptamine-2B receptor protein in the rat central nervous system. Neuroscience 1997; 76: 323–329.

    Article  CAS  PubMed  Google Scholar 

  78. Sah P, Lopez De Armentia M . Excitatory synaptic transmission in the lateral and central amygdala. Ann NY Acad Sci 2003; 985: 67–77.

    Article  CAS  PubMed  Google Scholar 

  79. Walker DL, Davis M . The role of amygdala glutamate receptors in fear learning, fear-potentiated startle, and extinction. Pharmacol Biochem Behav 2002; 71: 379–392.

    Article  CAS  PubMed  Google Scholar 

  80. Bird GC, Lash LL, Han JS, Zou X, Willis WD, Neugebauer V . Protein kinase A-dependent enhanced NMDA receptor function in pain-related synaptic plasticity in rat amygdala neurones. J Physiol 2005; 564 (Part 3): 907–921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Roozendaal B, Quirarte GL, McGaugh JL . Glucocorticoids interact with the basolateral amygdala beta-adrenoceptor--cAMP/cAMP/PKA system in influencing memory consolidation. Eur J Neurosci 2002; 15: 553–560.

    Article  PubMed  Google Scholar 

  82. Quartara L, Maggi CA . The tachykinin NK1 receptor. Part I: ligands and mechanisms of cellular activation. Neuropeptides 1997; 31: 537–563.

    Article  CAS  PubMed  Google Scholar 

  83. Hoover DB, Chang Y, Hancock JC, Zhang L . Actions of tachykinins within the heart and their relevance to cardiovascular disease. Jpn J Pharmacol 2000; 84: 367–373.

    Article  CAS  PubMed  Google Scholar 

  84. Butcher JW, De Felipe C, Smith AJ, Hunt SP, Paton JF . Comparison of cardiorespiratory reflexes in NK1 receptor knockout, heterozygous and wild-type mice in vivo. J Auton Nerv Syst 1998; 69: 89–95.

    Article  CAS  PubMed  Google Scholar 

  85. Saria A . The tachykinin NK1 receptor in the brain: pharmacology and putative functions. Eur J Pharmacol 1999; 375: 51–60.

    Article  CAS  PubMed  Google Scholar 

  86. Mantyh PW . Neurobiology of substance P and the NK1 receptor. J Clin Psychiatry 2002; 63 (Suppl 11): 6–10.

    CAS  PubMed  Google Scholar 

  87. Maggi CA . The effects of tachykinins on inflammatory and immune cells. Regul Pept 1997; 70: 75–90.

    Article  CAS  PubMed  Google Scholar 

  88. Chernajovsky Y, Gould DJ, Podhajcer OL . Gene therapy for autoimmune diseases: quo vadis? Nat Rev Immunol 2004; 4: 800–811.

    Article  CAS  PubMed  Google Scholar 

  89. Cao YQ, Mantyh PW, Carlson EJ, Gillespie AM, Epstein CJ, Basbaum AI . Primary afferent tachykinins are required to experience moderate to intense pain [see comments]. Nature 1998; 392: 390–394.

    Article  CAS  PubMed  Google Scholar 

  90. Zimmer A, Zimmer AM, Baffi J, Usdin T, Reynolds K, Konig M et al. Hypoalgesia in mice with a targeted deletion of the tachykinin 1 gene. Proc Natl Acad Sci USA 1998; 95: 2630–2635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hokfelt T, Pernow B, Wahren J . Substance P: a pioneer amongst neuropeptides. J Intern Med 2001; 249: 27–40.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Martin J Collinson for the kind gift of the SP antibody. We would also like to thank Arthur Buchberg for the gift of the anti-MEIS1 antibody. This work was funded by the Tenovus (Scotland) Trust. KM and SD were funded by BBSRC PhD Studentships. We would also like to thank Agnes Grout for providing the inspiration for this project.

Author information

Authors and Affiliations

  1. School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK

    S Davidson, K A Miller, A Dowell, A Gildea & A MacKenzie

Authors
  1. S Davidson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K A Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A Dowell
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Gildea
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A MacKenzie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A MacKenzie.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Davidson, S., Miller, K., Dowell, A. et al. A remote and highly conserved enhancer supports amygdala specific expression of the gene encoding the anxiogenic neuropeptide substance-P. Mol Psychiatry 11, 410–421 (2006). https://doi.org/10.1038/sj.mp.4001787

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001787

Keywords

This article is cited by

Search

Advanced search

Quick links