Cell and Tissue Research

, Volume 344, Issue 1, pp 1–11 | Cite as

Global daily dynamics of the pineal transcriptome

  • Diego M. Bustos
  • Michael J. Bailey
  • David Sugden
  • David A. Carter
  • Martin F. Rath
  • Morten Møller
  • Steven L. Coon
  • Joan L. Weller
  • David C. KleinEmail author
Mini Review


Transcriptome profiling of the pineal gland has revealed night/day differences in the expression of a major fraction of the genes active in this tissue, with two-thirds of these being nocturnal increases. A set of over 600 transcripts exhibit two-fold to >100-fold daily differences in abundance. These changes appear to be primarily attributable to adrenergic-cyclic-AMP-dependent mechanisms, which are controlled via a neural pathway that includes the suprachiasmatic nucleus, the master circadian oscillator. In addition to melatonin synthesis, night/day differences in gene expression impact genes associated with several specialized functions, including the immune/inflammation response, photo-transduction, and thyroid hormone/retinoic acid biology. The following nonspecialized cellular features are also affected: adhesion, cell cycle/cell death, cytoskeleton, DNA modification, endothelium, growth, RNA modification, small molecule biology, transcription factors, vesicle biology, signaling involving Ca2+, cyclic nucleotides, phospholipids, mitogen-activated protein kinases, the Wnt signaling pathway, and protein phosphorylation.


Pineal gland Suprachiasmatic nucleus Circadian rhythm Gene expression Transcriptome Microarray Systems biology 


  1. Arendt J (1994) Melatonin and the mammalian pineal gland, 1st edn. Chapman & Hall, New YorkGoogle Scholar
  2. Bailey MJ, Coon SL, Carter DA, Humphries A, Kim JS, Shi Q, Gaildrat P, Morin F, Ganguly S, Hogenesch JB et al (2009) Night/day changes in pineal expression of >600 genes: central role of adrenergic/cAMP signaling. J Biol Chem 284:7606–7622PubMedCrossRefGoogle Scholar
  3. Chik CL, Arnason TG, Dukewich WG, Price DM, Ranger A, Ho AK (2007) Histone H3 phosphorylation in the rat pineal gland: adrenergic regulation and diurnal variation. Endocrinology 148:1465–1472PubMedCrossRefGoogle Scholar
  4. Do MT, Kang SH, Xue T, Zhong H, Liao HW, Bergles DE, Yau KW (2009) Photon capture and signalling by melanopsin retinal ganglion cells. Nature 457:281–287PubMedCrossRefGoogle Scholar
  5. Estivill-Torrus G, Vitalis T, Fernandez-Llebrez P, Price DJ (2001) The transcription factor Pax6 is required for development of the diencephalic dorsal midline secretory radial glia that form the subcommissural organ. Mech Dev 109:215–224PubMedCrossRefGoogle Scholar
  6. Franco R, Casado V, Cortes A, Ferrada C, Mallol J, Woods A, Lluis C, Canela EI, Ferre S (2007) Basic concepts in G-protein-coupled receptor homo- and heterodimerization. ScientificWorldJournal 7:48–57PubMedGoogle Scholar
  7. Ganguly S, Grodzki C, Sugden D, Møller M, Odom S, Gaildrat P, Gery I, Siraganian RP, Rivera J, Klein DC (2007) Neural adrenergic/cyclic AMP regulation of the immunoglobulin E receptor alpha-subunit expression in the mammalian pinealocyte: a neuroendocrine/immune response link? J Biol Chem 282:32758–32764PubMedCrossRefGoogle Scholar
  8. Haldar-Misra C, Pevet P (1983) The influence of different 5-methoxyindoles on the process of protein/peptide secretion characterized by the formation of granular vesicles in the mouse pineal gland. An in vitro study. Cell Tissue Res 230:113–126PubMedCrossRefGoogle Scholar
  9. Hannibal J, Møller M, Ottersen OP, Fahrenkrug J (2000) PACAP and glutamate are co-stored in the retinohypothalamic tract. J Comp Neurol 418:147–155PubMedCrossRefGoogle Scholar
  10. Ho AK, Chik CL (1990) Post-receptor mechanism in dual receptors regulation of second messengers in rat pineal gland. Prog Clin Biol Res 342:139–145PubMedGoogle Scholar
  11. Ho AK, Chik CL (2010) Modulation of Aanat gene transcription in the rat pineal gland. J Neurochem 112:321–331PubMedCrossRefGoogle Scholar
  12. Ho AK, Price DM, Dukewich WG, Steinberg N, Arnason TG, Chik CL (2007) Acetylation of histone H3 and adrenergic-regulated gene transcription in rat pinealocytes. Endocrinology 148:4592–4600PubMedCrossRefGoogle Scholar
  13. Ho AK, Thomas TP, Chik CL, Anderson WB, Klein DC (1988) Protein kinase C: subcellular redistribution by increased Ca2+ influx. Evidence that Ca2+-dependent subcellular redistribution of protein kinase C is involved in potentiation of beta-adrenergic stimulation of pineal cAMP and cGMP by K+ and A23187. J Biol Chem 263:9292–9297PubMedGoogle Scholar
  14. Kanyo R, Price DM, Chik CL, Ho AK (2009) Salt-inducible kinase 1 in the rat pinealocyte: adrenergic regulation and role in arylalkylamine N-acetyltransferase gene transcription. Endocrinology 150:4221–4230PubMedCrossRefGoogle Scholar
  15. Kappers JA (1965) Survey of the innervation of the epiphysis cerebri and the accessory pineal organs of vertebrates. Prog Brain Res 10:87–153PubMedCrossRefGoogle Scholar
  16. Kim JS, Coon SL, Blackshaw S, Cepko CL, Møller M, Mukda S, Zhao WQ, Charlton CG, Klein DC (2005) Methionine adenosyltransferase:adrenergic-cAMP mechanism regulates a daily rhythm in pineal expression. J Biol Chem 280:677–684PubMedGoogle Scholar
  17. Kim JS, Bailey MJ, Ho AK, Møller M, Gaildrat P, Klein DC (2007) Daily rhythm in pineal phosphodiesterase (PDE) activity reflects adrenergic/3′, 5′-cyclic adenosine 5′-monophosphate induction of the PDE4B2 variant. Endocrinology 148:1475–1485PubMedCrossRefGoogle Scholar
  18. Kim JS, Coon SL, Weller JL, Blackshaw S, Rath MF, Møller M, Klein DC (2009) Muscleblind-like 2: circadian expression in the mammalian pineal gland is controlled by an adrenergic-cAMP mechanism. J Neurochem 110:756–764PubMedCrossRefGoogle Scholar
  19. Kim JS, Bailey MJ, Weller JL, Sugden D, Rath MF, Møller M, Klein DC (2010) Thyroid hormone and adrenergic signaling interact to control pineal expression of the dopamine receptor D4 gene (Drd4). Mol Cell Endocrinol 314:128–135PubMedCrossRefGoogle Scholar
  20. Klein DC (1985) Photoneural regulation of the mammalian pineal gland. Ciba Found Symp 117:38–56PubMedGoogle Scholar
  21. Klein DC (2004) The 2004 Aschoff/Pittendrigh lecture: theory of the origin of the pineal gland—a tale of conflict and resolution. J Biol Rhythms 19:264–279PubMedCrossRefGoogle Scholar
  22. Klein DC (2007) Arylalkylamine N-acetyltransferase: "the timezyme". J Biol Chem 282:4233–4237PubMedCrossRefGoogle Scholar
  23. Klein DC, Moore RY, Reppert SM (1991) Suprachiasmatic nucleus: the mind’s clock. Oxford University Press, New YorkGoogle Scholar
  24. Klein DC, Coon SL, Roseboom PH, Weller JL, Bernard M, Gastel JA, Zatz M, Iuvone PM, Rodriguez IR, Begay V et al (1997) The melatonin rhythm-generating enzyme: molecular regulation of serotonin N-acetyltransferase in the pineal gland. Recent Prog Horm Res 52:307–358PubMedGoogle Scholar
  25. Klein DC, Baler R, Roseboom PH, Weller JL, Bernard M, Gastel JA, Zatz M, Iuvone PM, Begay V, Falcon J et al (1999) The molecular basis of the pineal melatonin rhythm: regulation of serotonin N-acetylation. In: Lydic R, Baghdoyan HA (eds) Handbook of behavioral state control: cellular and molecular mechanisms. CRC Press, Boca Raton, pp 45–55Google Scholar
  26. Klein DC, Bailey MJ, Carter DA, Kim JS, Shi Q, Ho AK, Chik CL, Gaildrat P, Morin F, Ganguly S et al (2010) Pineal function: impact of microarray analysis. Mol Cell Endocrinol 314:170–183PubMedCrossRefGoogle Scholar
  27. Lolley RN, Craft CM, Lee RH (1992) Photoreceptors of the retina and pinealocytes of the pineal gland share common components of signal transduction.Neurochem Res 17:81–89PubMedCrossRefGoogle Scholar
  28. Marquardt T, Ashery-Padan R, Andrejewski N, Scardigli R, Guillemot F, Gruss P (2001) Pax6 is required for the multipotent state of retinal progenitor cells. Cell 105:43–55PubMedCrossRefGoogle Scholar
  29. Mata MM, Schrier BK, Klein DC, Weller JL, Chiou CY (1976) On GABA function and physiology in the pineal gland. Brain Res 118:383–394PubMedCrossRefGoogle Scholar
  30. Møller M (1976) The ultrastructure of the human fetal pineal gland. II. Innervation and cell junctions. Cell Tissue Res 169:7–21PubMedCrossRefGoogle Scholar
  31. Møller M (1979) Presence of a pineal nerve (nervus pinealis) in fetal mammals. Prog Brain Res 52:103–106PubMedCrossRefGoogle Scholar
  32. Møller M, Baeres FM (2002) The anatomy and innervation of the mammalian pineal gland. Cell Tissue Res 309:139–150PubMedCrossRefGoogle Scholar
  33. Møller M, Ingild A, Bock E (1978a) Immunohistochemical demonstration of S-100 protein and GFA protein in interstitial cells of rat pineal gland. Brain Res 140:1–13PubMedCrossRefGoogle Scholar
  34. Møller M, Deurs B van, Westergaard E (1978b) Vascular permeability to proteins and peptides in the mouse pineal gland. Cell Tissue Res 195:1–15PubMedCrossRefGoogle Scholar
  35. Møller M, Rath MF, Klein DC (2006) The perivascular phagocyte of the mouse pineal gland: an antigen-presenting cell. Chronobiol Int 23:393–401PubMedCrossRefGoogle Scholar
  36. Moore RY (1999) A clock for the ages. Science 284:2102–2103PubMedCrossRefGoogle Scholar
  37. Moore RY, Lenn NJ (1972) A retinohypothalamic projection in the rat. J Comp Neurol 146:1–14PubMedCrossRefGoogle Scholar
  38. Moore RY, Speh JC, Leak RK (2002) Suprachiasmatic nucleus organization. Cell Tissue Res 309:89–98PubMedCrossRefGoogle Scholar
  39. Moriyama Y, Yamamoto A (1995) Vesicular L-glutamate transporter in microvesicles from bovine pineal glands. Driving force, mechanism of chloride anion activation, and substrate specificity. J Biol Chem 270:22314–22320PubMedCrossRefGoogle Scholar
  40. Parfitt AG, Klein DC (1976) Sympathetic nerve endings in the pineal gland protect against acute stress-induced increase in N-acetyltransferase (EC activity. Endocrinology 99:840–851PubMedCrossRefGoogle Scholar
  41. Price DM, Kanyo R, Steinberg N, Chik CL, Ho AK (2009) Nocturnal activation of aurora C in rat pineal gland: its role in the norepinephrine-induced phosphorylation of histone H3 and gene expression. Endocrinology 150:2334–2341PubMedCrossRefGoogle Scholar
  42. Provencio I, Jiang G, De Grip WJ, Hayes WP, Rollag MD (1998) Melanopsin: an opsin in melanophores, brain, and eye. Proc Natl Acad Sci USA 95:340–345PubMedCrossRefGoogle Scholar
  43. Rath MF, Munoz E, Ganguly S, Morin F, Shi Q, Klein DC, Møller M (2006) Expression of the Otx2 homeobox gene in the developing mammalian brain: embryonic and adult expression in the pineal gland. J Neurochem 97:556–566PubMedCrossRefGoogle Scholar
  44. Rath MF, Bailey MJ, Kim JS, Ho AK, Gaildrat P, Coon SL, Møller M, Klein DC (2009) Developmental and diurnal dynamics of Pax4 expression in the mammalian pineal gland: nocturnal down-regulation is mediated by adrenergic-cyclic adenosine 3′, 5′-monophosphate signaling. Endocrinology 150:803–811PubMedCrossRefGoogle Scholar
  45. Roseboom PH, Coon SL, Baler R, McCune SK, Weller JL, Klein DC (1996) Melatonin synthesis: analysis of the more than 150-fold nocturnal increase in serotonin N-acetyltransferase messenger ribonucleic acid in the rat pineal gland. Endocrinology 137:3033–3045PubMedCrossRefGoogle Scholar
  46. Sugden D, Klein DC (1983) Adrenergic stimulation of rat pineal hydroxyindole-O-methyltransferase. Brain Res 265:348–351PubMedCrossRefGoogle Scholar
  47. Sugden D, Klein DC (1984) Rat pineal alpha 1-adrenoceptors: identification and characterization using [125I]iodo-2-[beta-(4-hydroxyphenyl)-ethylaminomethyl]tetralone. Endocrinology 114:435–440PubMedCrossRefGoogle Scholar
  48. Sugden D, Klein DC (1987) A cholera toxin substrate regulates cyclic GMP content of rat pinealocytes. J Biol Chem 262:7447–7450PubMedGoogle Scholar
  49. Sugden D, Klein DC (1988) Activators of protein kinase C act at a postreceptor site to amplify cyclic AMP production in rat pinealocytes. J Neurochem 50:149–155PubMedCrossRefGoogle Scholar
  50. Sugden D, Vanecek J, Klein DC, Thomas TP, Anderson WB (1985) Activation of protein kinase C potentiates isoprenaline-induced cyclic AMP accumulation in rat pinealocytes. Nature 314:359–361PubMedCrossRefGoogle Scholar
  51. Tsai SY, McNulty JA (1999) Interleukin-1beta expression in the pineal gland of the rat. J Pineal Res 27:42–48PubMedCrossRefGoogle Scholar
  52. Tsai SY, O'Brien TE, McNulty JA (2001a) Microglia play a role in mediating the effects of cytokines on the structure and function of the rat pineal gland. Cell Tissue Res 303:423–431PubMedCrossRefGoogle Scholar
  53. Tsai SY, Schluns KS, Le PT, McNulty JA (2001b) TGF-beta1 and IL-6 expression in rat pineal gland is regulated by norepinephrine and interleukin-1beta. Histol Histopathol 16:1135–1141PubMedGoogle Scholar
  54. Van Gelder RN (2001) Non-visual ocular photoreception. Ophthalmic Genet 22:195–205PubMedCrossRefGoogle Scholar
  55. Vanecek J, Sugden D, Weller J, Klein DC (1985) Atypical synergistic alpha 1- and beta-adrenergic regulation of adenosine 3′, 5′-monophosphate and guanosine 3′, 5′-monophosphate in rat pinealocytes. Endocrinology 116:2167–2173PubMedCrossRefGoogle Scholar
  56. Vigh-Teichmann I, Korf HW, Oksche A, Vigh B (1982) Opsin-immunoreactive outer segments and acetylcholinesterase-positive neurons in the pineal complex of Phoxinus phoxinus (Teleostei, Cyprinidae). Cell Tissue Res 227:351–369PubMedCrossRefGoogle Scholar
  57. Yatsushiro S, Yamada H, Kozaki S, Kumon H, Michibata H, Yamamoto A, Moriyama Y (1997) L-aspartate but not the D form is secreted through microvesicle-mediated exocytosis and is sequestered through Na+-dependent transporter in rat pinealocytes. J Neurochem 69:340–347PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag (outside the USA) 2011

Authors and Affiliations

  • Diego M. Bustos
    • 1
  • Michael J. Bailey
    • 2
  • David Sugden
    • 3
  • David A. Carter
    • 4
  • Martin F. Rath
    • 5
  • Morten Møller
    • 5
  • Steven L. Coon
    • 6
  • Joan L. Weller
    • 6
  • David C. Klein
    • 6
    • 7
    Email author
  1. 1.Instituto Tecnológico de Chascomús (Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús)ChascomúsArgentina
  2. 2.Department of Poultry ScienceTexas A & M UniversityCollege StationUSA
  3. 3.Division of Reproduction and Endocrinology, School of Biomedical and Health SciencesKing’s College LondonLondonUK
  4. 4.School of BiosciencesCardiff UniversityCardiffUK
  5. 5.Department of Neuroscience and Pharmacology, Faculty of Health SciencesUniversity of CopenhagenCopenhagenDenmark
  6. 6.Section on Neuroendocrinology, Program on Developmental Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNational Institutes of HealthBethesdaUSA
  7. 7.BethesdaUSA

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