BRAIN and NERVE－神経研究の進歩66巻6号

2014年06月発行

総説

哺乳類概日時計の階層的制御

著者： 大出晃士¹² 上田泰己¹²³

所属機関： ¹東京大学大学院医学系研究科システムズ薬理学教室 ²理化学研究所生命システム研究センター ³理化学研究所発生・再生科学総合研究センター

ページ範囲：P.681 - P.689

文献概要

概日時計は，睡眠覚醒サイクルに象徴される行動・生理活性の日内変動を生み出す機構である。その周期性は，時計遺伝子と呼ばれる一連の転写因子の転写活性が，負のフィードバック制御を介して自律的に増減を繰り返すことでもたらされる。時計遺伝子の周期的発現は全身のほぼすべての細胞にみられる。各細胞の概日時計の位相は，視交叉上核と呼ばれる脳領域によって支配的に制御され，全身の細胞の概日時刻が同期される。本稿では，分子から細胞・個体に至る概日時計制御の階層性を紹介する。

参考文献

1) Woelfle MA, Ouyang Y, Phanvijhitsiri K, Johnson CH: The adaptive value of circadian clocks: an experimental assessment in cyanobacteria. Curr Biol 14: 1481-1486, 2004

2) Stephan FK, Zucker I: Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci U S A 69: 1583-1586, 1972

3) Moore RY, Eichler VB: Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res 42: 201-206, 1972

4) Ralph MR, Foster RG, Davis FC, Menaker M: Transplanted suprachiasmatic nucleus determines circadian period. Science 247: 975-978, 1990

5) Green DJ, Gillette R: Circadian rhythm of firing rate recorded from single cells in the rat suprachiasmatic brain slice. Brain Res 245: 198-200, 1982

6) Yamazaki S, Takahashi JS: Real-time luminescence reporting of circadian gene expression in mammals. Methods Enzymol 393: 288-301, 2005

7) Welsh DK, Logothetis DE, Meister M, Reppert SM: Individual neurons dissociated from rat suprachiasmatic nucleus express independently phased circadian firing rhythms. Neuron 14: 697-706, 1995

8) Herzog ED, Takahashi JS, Block GD: Clock controls circadian period in isolated suprachiasmatic nucleus neurons. Nat Neurosci 1: 708-713, 1998

9) Liu AC, Welsh DK, Ko CH, Tran HG, Zhang EE, et al: Intercellular coupling confers robustness against mutations in the SCN circadian clock network. Cell 129: 605-616, 2007

10) Webb AB, Angelo N, Huettner JE, Herzog ED: Intrinsic, nondeterministic circadian rhythm generation in identified mammalian neurons. Proc Natl Acad Sci U S A 106: 16493-16498, 2009

11) Lee JE, Atkins N Jr, Hatcher NG, Zamdborg L, Gillette MU, et al: Endogenous peptide discovery of the rat circadian clock: a focused study of the suprachiasmatic nucleus by ultrahigh performance tandem mass spectrometry. Mol Cell Proteomics 9: 285-297, 2010

12) Abrahamson EE, Moore RY: Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections. Brain Res 916: 172-191, 2001

13) Maywood ES, Chesham JE, O'Brien JA, Hastings MH: A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits. Proc Natl Acad Sci U S A 108: 14306-14311, 2011

14) Li JD, Burton KJ, Zhang C, Hu SB, Zhou QY: Vasopressin receptor V1a regulates circadian rhythms of locomotor activity and expression of clock-controlled genes in the suprachiasmatic nuclei. Am J Physiol Regul Integr Comp Physiol 296: R824-830, 2009

15) Yamaguchi Y, Suzuki T, Mizoro Y, Kori H, Okada K, et al: Mice genetically deficient in vasopressin V1a and V1b receptors are resistant to jet lag. Science 342: 85-90, 2013

16) An S, Harang R, Meeker K, Granados-Fuentes D, Tsai CA, et al: A neuropeptide speeds circadian entrainment by reducing intercellular synchrony. Proc Natl Acad Sci U S A 110: E4355-4361, 2013

17) Deurveilher S, Semba K: Indirect projections from the suprachiasmatic nucleus to major arousal-promoting cell groups in rat: implications for the circadian control of behavioural state. Neuroscience 130: 165-183, 2005

18) Silver R, LeSauter J, Tresco PA, Lehman MN: A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms. Nature 382: 810-813, 1996

19) Bunger MK, Wilsbacher LD, Moran SM, Clendenin C, Radcliffe LA, et al: Mop3 is an essential component of the master circadian pacemaker in mammals. Cell 103: 1009-1017, 2000

20) DeBruyne JP, Weaver DR, Reppert SM: CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nat Neurosci 10: 543-545, 2007

21) Zheng B, Albrecht U, Kaasik K, Sage M, Lu W, et al: Nonredundant roles of the mPer1 and mPer2 genes in the mammalian circadian clock. Cell 105: 683-694, 2001

22) Bae K, Jin X, Maywood ES, Hastings MH, Reppert SM, et al: Differential functions of mPer1, mPer2, and mPer3 in the SCN circadian clock. Neuron 30: 525-536, 2001

23) Vitaterna MH, Selby CP, Todo T, Niwa H, Thompson C, et al: Differential regulation of mammalian period genes and circadian rhythmicity by cryptochromes 1 and 2．Proc Natl Acad Sci U S A 96: 12114-12119, 1999

24) van der Horst GT, Muijtjens M, Kobayashi K, Takano R, Kanno S, et al: Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms. Nature 398: 627-630, 1999

25) Balsalobre A, Damiola F, Schibler U: A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell 93: 929-937, 1998

26) Welsh DK, Yoo SH, Liu AC, Takahashi JS, Kay SA: Bioluminescence imaging of individual fibroblasts reveals persistent, independently phased circadian rhythms of clock gene expression. Curr Biol 14: 2289-2295, 2004

27) Etchegaray JP, Lee C, Wade PA, Reppert SM: Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 421: 177-182, 2003

28) Ripperger JA, Schibler U: Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions. Nat Genet 38: 369-374, 2006

29) Katada S, Sassone-Corsi P: The histone methyltransferase MLL1 permits the oscillation of circadian gene expression. Nat Struct Mol Biol 17: 1414-1421, 2010

30) DiTacchio L, Le HD, Vollmers C, Hatori M, Witcher M, et al: Histone lysine demethylase JARID1a activates CLOCK-BMAL1 and influences the circadian clock. Science 333: 1881-1885, 2011

31) Asher G, Gatfield D, Stratmann M, Reinke H, Dibner C, et al: SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 134: 317-328, 2008

-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 134: 329-340, 2008

33) Duong HA, Robles MS, Knutti D, Weitz CJ: A molecular mechanism for circadian clock negative feedback. Science 332: 1436-1439, 2011

34) Duong HA, Weitz CJ: Temporal orchestration of repressive chromatin modifiers by circadian clock Period complexes. Nat Struct Mol Biol 21: 126-132, 2014

35) Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, et al: mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 98: 193-205, 1999

36) Chen R, Schirmer A, Lee Y, Lee H, Kumar V, et al: Rhythmic PER abundance defines a critical nodal point for negative feedback within the circadian clock mechanism. Mol Cell 36: 417-430, 2009

37) Padmanabhan K, Robles MS, Westerling T, Weitz CJ: Feedback regulation of transcriptional termination by the mammalian circadian clock PERIOD complex. Science 337: 599-602, 2012

38) Lin C, Todo T: The cryptochromes. Genome Biol 6: 220, 2005

39) Hsu DS, Zhao X, Zhao S, Kazantsev A, Wang RP, et al: Putative human blue-light photoreceptors hCRY1 and hCRY2 are flavoproteins. Biochemistry 35: 13871-13877, 1996

40) Hitomi K, DiTacchio L, Arvai AS, Yamamoto J, Kim ST, et al: Functional motifs in the (6-4) photolyase crystal structure make a comparative framework for DNA repair photolyases and clock cryptochromes. Proc Natl Acad Sci U S A 106: 6962-6967, 2009

41) Froy O, Chang DC, Reppert SM: Redox potential: differential roles in dCRY and mCRY1 functions. Curr Biol 12: 147-152, 2002

42) McIntosh BE, Hogenesch JB, Bradfield CA: Mammalian Per-Arnt-Sim proteins in environmental adaptation. Annu Rev Physiol 72: 625-645, 2010

43) Dioum EM, Rutter J, Tuckerman JR, Gonzalez G, Gilles-Gonzalez MA, et al: NPAS2: a gas-responsive transcription factor. Science 298: 2385-2387, 2002

44) Yang J, Kim KD, Lucas A, Drahos KE, Santos CS, et al: A novel heme-regulatory motif mediates heme-dependent degradation of the circadian factor period 2．Mol Cell Biol 28: 4697-4711, 2008

45) Lukat-Rodgers GS, Correia C, Botuyan MV, Mer G, Rodgers KR: Heme-based sensing by the mammalian circadian protein CLOCK. Inorg Chem 49: 6349-6365, 2010

46) Kaasik K, Lee CC: Reciprocal regulation of haem biosynthesis and the circadian clock in mammals. Nature 430: 467-471, 2004

47) Kitanishi K, Igarashi J, Hayasaka K, Hikage N, Saiful I, et al: Heme-binding characteristics of the isolated PAS-A domain of mouse Per2, a transcriptional regulatory factor associated with circadian rhythms. Biochemistry 47: 6157-6168, 2008

48) Hayasaka K, Kitanishi K, Igarashi J, Shimizu T: Heme-binding characteristics of the isolated PAS-B domain of mouse Per2, a transcriptional regulatory factor associated with circadian rhythms. Biochim Biophys Acta 1814: 326-333, 2011

49) Ye R, Selby CP, Ozturk N, Annayev Y, Sancar A: Biochemical analysis of the canonical model for the mammalian circadian clock. J Biol Chem 286: 25891-25902, 2011

50) Huang N, Chelliah Y, Shan Y, Taylor CA, Yoo SH, et al: Crystal structure of the heterodimeric CLOCK: BMAL1 transcriptional activator complex. Science 337: 189-194, 2012

51) Hennig S, Strauss HM, Vanselow K, Yildiz O, Schulze S, et al: Structural and functional analyses of PAS domain interactions of the clock proteins Drosophila PERIOD and mouse PERIOD2．PLOS Biol 7: e94, 2009

52) Kucera N, Schmalen I, Hennig S, Ollinger R, Strauss HM, et al: Unwinding the differences of the mammalian PERIOD clock proteins from crystal structure to cellular function. Proc Natl Acad Sci U S A 109: 3311-3316, 2012

53) Czarna A, Berndt A, Singh HR, Grudziecki A, Ladurner AG, et al: Structures of Drosophila cryptochrome and mouse cryptochrome1 provide insight into circadian function. Cell 153: 1394-1405, 2013

54) Xing W, Busino L, Hinds TR, Marionni ST, Saifee NH, et al: SCF (FBXL3) ubiquitin ligase targets cryptochromes at their cofactor pocket. Nature 496: 64-68, 2013

55) Jones CR, Campbell SS, Zone SE, Cooper F, DeSano A, et al: Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nat Med 5: 1062-1065, 1999

56) Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, et al: Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature 434: 640-644, 2005

57) Toh KL, Jones CR, He Y, Eide EJ, Hinz WA, et al: An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 291: 1040-1043, 2001

58) Lowrey PL, Shimomura K, Antoch MP, Yamazaki S, Zemenides PD, et al: Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 288: 483-492, 2000

59) Shirogane T, Jin J, Ang XL, Harper JW: SCFbeta-TRCP controls clock-dependent transcription via casein kinase 1-dependent degradation of the mammalian period-1 (Per1) protein. J Biol Chem 280: 26863-26872, 2005

60) Eide EJ, Woolf MF, Kang H, Woolf P, Hurst W, et al: Control of mammalian circadian rhythm by CKIε-regulated proteasome-mediated PER2 degradation. Mol Cell Biol 25: 2795-2807, 2005

61) Meng QJ, Logunova L, Maywood ES, Gallego M, Lebiecki J, et al: Setting clock speed in mammals: the CK1 epsilon tau mutation in mice accelerates circadian pacemakers by selectively destabilizing PERIOD proteins. Neuron 58: 78-88, 2008

62) Gallego M, Eide EJ, Woolf MF, Virshup DM, Forger DB: An opposite role for tau in circadian rhythms revealed by mathematical modeling. Proc Natl Acad Sci U S A 103: 10618-10623, 2006

63) Isojima Y, Nakajima M, Ukai H, Fujishima H, Yamada RG, et al: CKIε/δ-dependent phosphorylation is a temperature-insensitive, period-determining process in the mammalian circadian clock. Proc Natl Acad Sci U S A 106: 15744-15749, 2009

64) Chen Z, Yoo SH, Park YS, Kim KH, Wei S, et al: Identification of diverse modulators of central and peripheral circadian clocks by high-throughput chemical screening. Proc Natl Acad Sci U S A 109: 101-106, 2012

65) Flotow H, Graves PR, Wang AQ, Fiol CJ, Roeske RW, et al: Phosphate groups as substrate determinants for casein kinase I action. J Biol Chem 265: 14264-14269, 1990

66) Vanselow K, Vanselow JT, Westermark PO, Reischl S, Maier B, et al: Differential effects of PER2 phosphorylation: molecular basis for the human familial advanced sleep phase syndrome (FASPS). Genes Dev 20: 2660-2672, 2006

67) Xu Y, Toh KL, Jones CR, Shin JY, Fu YH, et al: Modeling of a human circadian mutation yields insights into clock regulation by PER2．Cell 128: 59-70, 2007

68) Chiu JC, Ko HW, Edery I: NEMO/NLK phosphorylates PERIOD to initiate a time-delay phosphorylation circuit that sets circadian clock speed. Cell 145: 357-370, 2011

69) Querfurth C, Diernfellner AC, Gin E, Malzahn E, Hofer T, et al: Circadian conformational change of the Neurospora clock protein FREQUENCY triggered by clustered hyperphosphorylation of a basic domain. Mol Cell 43: 713-722, 2011

70) Siepka SM, Yoo SH, Park J, Song W, Kumar V, et al: Circadian mutant Overtime reveals F-box protein FBXL3 regulation of Cryptochrome and Period gene expression. Cell 129: 1011-1023, 2007

71) Busino L, Bassermann F, Maiolica A, Lee C, Nolan PM, et al: SCFFbxl3 controls the oscillation of the circadian clock by directing the degradation of cryptochrome proteins. Science 316: 900-904, 2007

72) Godinho SI, Maywood ES, Shaw L, Tucci V, Barnard AR, et al: The after-hours mutant reveals a role for Fbxl3 in determining mammalian circadian period. Science 316: 897-900, 2007

73) Gao P, Yoo SH, Lee KJ, Rosensweig C, Takahashi JS, et al: Phosphorylation of the cryptochrome 1 C-terminal tail regulates circadian period length. J Biol Chem 288: 35277-35286, 2013

74) Lamia KA, Sachdeva UM, DiTacchio L, Williams EC, Alvarez JG, et al: AMPK regulates the circadian clock by cryptochrome phosphorylation and degradation. Science 326: 437-440, 2009

75) Hirano A, Yumimoto K, Tsunematsu R, Matsumoto M, Oyama M, et al: FBXL21 regulates oscillation of the circadian clock through ubiquitination and stabilization of cryptochromes. Cell 152: 1106-1118, 2013

76) Yoo SH, Mohawk JA, Siepka SM, Shan Y, Huh SK, et al: Competing E3 ubiquitin ligases govern circadian periodicity by degradation of CRY in nucleus and cytoplasm. Cell 152: 1091-1105, 2013

77) Hirota T, Lee JW, St John PC, Sawa M, Iwaisako K, et al: Identification of small molecule activators of cryptochrome. Science 337: 1094-1097, 2012