title: Mammalian target of rapamycin signaling modulates photic entrainment of the suprachiasmatic circadian clock.
abstract: Inducible gene expression appears to be an essential event that couples light to entrainment of the master mammalian circadian clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Recently, we reported that light triggers phase-dependent activation of the mammalian target of rapamycin (mTOR) signaling pathway, a major regulator of protein synthesis, in the SCN, thus raising the possibility that mTOR-evoked mRNA translation contributes to clock entrainment. Here, we used a combination of cellular, molecular, and behavioral assays to address this question. To this end, we show that the in vivo infusion of the mTOR inhibitor rapamycin led to a significant attenuation of the phase-delaying effect of early-night light. Conversely, disruption of mTOR during the late night augmented the phase-advancing effect of light. To assess the role of mTOR signaling within the context of molecular entrainment, the effects of rapamycin on light-induced expression of PERIOD1 and PERIOD2 were examined. At both the early- and late-night time points, abrogation of mTOR signaling led to a significant attenuation of light-evoked PERIOD protein expression. Our results also reveal that light-induced mTOR activation leads to the translation of mRNAs with a 5'-terminal oligopyrimidine tract such as eukaryotic elongation factor 1A and the immediate early gene JunB. Together, these data indicate that the mTOR pathway functions as potent and selective regulator of light-evoked protein translation and SCN clock entrainment.
authors.affiliation: Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Ruifeng
authors.initials: R
authors.lastname: Cao
authors.forename: Aiqing
authors.initials: A
authors.lastname: Li
authors.forename: Hee-yeon
authors.initials: HY
authors.lastname: Cho
authors.forename: Boyoung
authors.initials: B
authors.lastname: Lee
authors.forename: Karl
authors.initials: K
authors.lastname: Obrietan
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation; D007276:Injections, Intraventricular; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008027:Light; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D020648:Peptide Elongation Factor 1 / Q000378:metabolism; D056950:Period Circadian Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology*; D013493:Suprachiasmatic Nucleus / Q000187:drug effects* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D015533:Transcriptional Activation
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D020648:Peptide Elongation Factor 1; D056950:Period Circadian Proteins; D016755:Proto-Oncogene Proteins c-jun; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
references.citation: Cell Metab. 2009 Apr;9(4):362-74
references.pmid: 19356717
references.citation: Annu Rev Pharmacol Toxicol. 2002;42:135-63
references.pmid: 11807168
references.citation: Genes Dev. 2004 Aug 15;18(16):1926-45
references.pmid: 15314020
references.citation: J Physiol. 1996 Feb 1;490 ( Pt 3):703-11
references.pmid: 8683469
references.citation: J Biol Rhythms. 1990 Summer;5(2):159-67
references.pmid: 2133125
references.citation: Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1432-7
references.pmid: 9465032
references.citation: J Biol Rhythms. 2001 Apr;16(2):100-4
references.pmid: 11302552
references.citation: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7728-33
references.pmid: 12032351
references.citation: Am J Physiol. 1993 Nov;265(5 Pt 2):R1191-8
references.pmid: 7902017
references.citation: Hum Mol Genet. 2006 Oct 15;15 Spec No 2:R271-7
references.pmid: 16987893
references.citation: J Neurosci. 1990 Nov;10(11):3685-94
references.pmid: 2230953
references.citation: Neuron. 2007 Jun 7;54(5):813-29
references.pmid: 17553428
references.citation: Mol Cells. 2008 Jun 30;25(4):538-44
references.pmid: 18443410
references.citation: Growth Factors. 2007 Aug;25(4):209-26
references.pmid: 18092230
references.citation: J Neurosci. 2005 Jun 1;25(22):5305-13
references.pmid: 15930378
references.citation: J Neurosci. 2003 Apr 1;23(7):3085-93
references.pmid: 12684495
references.citation: J Biol Chem. 1998 Jun 26;273(26):16621-9
references.pmid: 9632736
references.citation: Neuroreport. 2001 Jan 22;12(1):127-31
references.pmid: 11201072
references.citation: J Neurosci. 2005 Jun 15;25(24):5833-43
references.pmid: 15958750
references.citation: Eur J Neurosci. 2004 Feb;19(4):1105-9
references.pmid: 15009158
references.citation: Blood. 2007 Nov 1;110(9):3374-83
references.pmid: 17690253
references.citation: Semin Cell Dev Biol. 2005 Feb;16(1):29-37
references.pmid: 15659337
references.citation: BMC Neurosci. 2006 Feb 16;7:15
references.pmid: 16483357
references.citation: Neuron. 2008 Dec 10;60(5):832-45
references.pmid: 19081378
references.citation: Cell Tissue Res. 2002 Jul;309(1):73-88
references.pmid: 12111538
references.citation: Curr Biol. 2008 Sep 9;18(17):1269-77
references.pmid: 18722121
references.citation: Mol Biol Rep. 1994 May;19(3):161-70
references.pmid: 7969104
references.citation: Neuron. 2009 Jan 15;61(1):10-26
references.pmid: 19146809
references.citation: Mol Cell Biol. 2008 May;28(9):2996-3007
references.pmid: 18316404
references.citation: EMBO J. 1997 Jun 16;16(12):3693-704
references.pmid: 9218810
references.citation: Brain Res. 1996 Nov 18;740(1-2):285-90
references.pmid: 8973826
references.citation: J Biol Chem. 2003 Jan 10;278(2):718-23
references.pmid: 12409294
references.citation: Science. 1992 Mar 20;255(5051):1581-4
references.pmid: 1549784
references.citation: Curr Opin Cell Biol. 2005 Dec;17(6):596-603
references.pmid: 16226444
references.citation: Trends Biochem Sci. 2009 Jun;34(6):311-8
references.pmid: 19464896
references.citation: J Neurochem. 2006 Jul;98(1):248-57
references.pmid: 16805811
references.citation: Brain Res. 1995 Sep 25;693(1-2):1-7
references.pmid: 8653396
references.citation: J Biol Chem. 1999 Jun 18;274(25):17748-56
references.pmid: 10364217
references.citation: Biochem J. 2007 Apr 15;403(2):217-34
references.pmid: 17376031
references.citation: J Biol Chem. 2002 Aug 16;277(33):29519-25
references.pmid: 12042309
references.citation: Proc Natl Acad Sci U S A. 1994 May 10;91(10):4441-5
references.pmid: 8183928
references.citation: Eur J Neurosci. 2002 Oct;16(8):1531-40
references.pmid: 12405967
references.citation: J Neurosci. 2005 Aug 3;25(31):7199-209
references.pmid: 16079402
references.citation: Nature. 2002 Aug 29;418(6901):935-41
references.pmid: 12198538
references.citation: Curr Biol. 2003 Feb 4;13(3):189-98
references.pmid: 12573214
references.citation: Front Biosci. 2003 May 01;8:s285-93
references.pmid: 12700026
references.citation: Eur J Neurosci. 2003 Nov;18(9):2552-62
references.pmid: 14622156
references.citation: Neuron. 1998 Jun;20(6):1103-10
references.pmid: 9655499
references.citation: Nat Neurosci. 1998 Dec;1(8):693-700
references.pmid: 10196585
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13680-5
references.pmid: 14578450
references.citation: Science. 2006 May 12;312(5775):927-30
references.pmid: 16690869
references.citation: Genes Dev. 2009 Jan 1;23(1):1-11
references.pmid: 19136621
references.citation: J Neurosci. 2004 Jul 14;24(28):6352-61
references.pmid: 15254091
references.citation: Cell. 1997 Dec 26;91(7):1055-64
references.pmid: 9428527
references.citation: J Biol Rhythms. 1992 Summer;7(2):125-36
references.pmid: 1611128
references.citation: Nature. 1971 Jun 11;231(5302):395-7
references.pmid: 4931010
references.citation: Mol Cell Neurosci. 2008 Jul;38(3):312-24
references.pmid: 18468454
references.citation: J Neurophysiol. 2002 Sep;88(3):1374-86
references.pmid: 12205158
references.citation: Curr Opin Cell Biol. 1993 Dec;5(6):955-60
references.pmid: 7907492
references.citation: Curr Biol. 1998 Mar 26;8(7):R248-50
references.pmid: 9545190
references.citation: RNA. 2007 May;13(5):745-55
references.pmid: 17400819
references.citation: Biochem Soc Trans. 2009 Feb;37(Pt 1):227-31
references.pmid: 19143637
references.citation: Cell. 1997 Dec 26;91(7):1043-53
references.pmid: 9428526
references.citation: Mutat Res. 2009 Jul-Aug;682(1):7-12
references.pmid: 19167516
references.citation: J Neurosci. 1999 Feb 1;19(3):1115-21
references.pmid: 9920673
references.citation: Cell. 2006 Feb 10;124(3):471-84
references.pmid: 16469695
references.citation: Am J Physiol. 1990 Jan;258(1 Pt 2):R256-62
references.pmid: 2154135