Mammalian target of rapamycin signaling modulates photic entrainment of the suprachiasmatic circadian clock.
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.
Cao
Ruifeng
R
Department of Neuroscience, Ohio State University, Columbus, Ohio 43210, USA.
Li
Aiqing
A
Cho
Hee-yeon
HY
Lee
Boyoung
B
Obrietan
Karl
K
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
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
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