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Mammalian Target of Rapamycin Signaling and the Suprachiasmatic Circadian Clock

Cao, Ruifeng
http://rave.ohiolink.edu/etdc/view?acc_num=osu1290199441

Abstract Details

2010, Doctor of Philosophy, Ohio State University, Neuroscience Graduate Studies Program.
Circadian (~24 hr) rhythmicity is a prevalent feature of virtually all the living organisms on the earth. This intrinsic property influences every aspect of life activities. In mammals, the master internal clock is localized in the suprachiasmatic nucleus (SCN) of the hypothalamus. Rhythmic clock gene expression constitutes the molecular basis of clock oscillation. As an important feature of the clock, it can be reset by signaling events that impinge on clock gene expression. There has been significant interest in unraveling the intracellular signal transduction pathways that couple extracellular signals to clock gene expression. Along these lines, our lab has identified a pivotal role of the p42/44 mitogen-activated protein kinase (MAPK) signaling pathway in the clock resetting process. As a continuation of this line of research, my thesis project is focused on the role of the mammalian target of rapamycin (mTOR) pathway in the circadian clock timing and entrainment. I found that brief light exposure during the subjective night, but not during the subjective day, triggered rapid phosphorylation (a marker of catalytic activity) of the mTOR translation effectors p70 S6K, ribosomal S6 protein (S6) and 4E-BP1 and MAPK cascade is an essential intermediate that couples light to mTOR. I also found that mTOR inhibition 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. These 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. Further, I observed the mTOR activity in the SCN under free-running condition. Using phosphorylated S6 ribosomal protein (pS6) as a marker of mTOR activity, I found that mTOR cascade exhibited maximal activity during the subjective day, and minimal expression during the late night. Using a transgenic period1 reporter gene mouse strain, I found a statistically significant cellular level correlation between pS6 and period1 gene expression over the circadian cycle. Interestingly, this cellular level correlation between mTOR activity and period1 transcription appears to be specific, since a similar expression profile for pS6 and Period2 or c-fos expression was not detected. Together these data suggest that the mTOR pathway is under the control of the SCN clock, and indicate that mTOR signaling may contribute to distinct aspects of the molecular clock timing process.
Karl Obrietan, PhD (Advisor)
Randy Nelson, PhD (Committee Member)
John Oberdick, PhD (Committee Member)
Glenn Lin, PhD (Committee Member)
129 p.
Neurosciences
circadian clock; mTOR; light; entrainment; Period1; Period2; S6K1; 4E-BP1; phase delay; phase advance; MSK; MAPK

Recommended Citations

Citations

  • Cao, R. (2010). Mammalian Target of Rapamycin Signaling and the Suprachiasmatic Circadian Clock [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1290199441

    APA Style (7th edition)

  • Cao, Ruifeng. Mammalian Target of Rapamycin Signaling and the Suprachiasmatic Circadian Clock. 2010. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1290199441.

    MLA Style (8th edition)

  • Cao, Ruifeng. "Mammalian Target of Rapamycin Signaling and the Suprachiasmatic Circadian Clock." Doctoral dissertation, Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1290199441

    Chicago Manual of Style (17th edition)

osu1290199441
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This open access ETD is published by The Ohio State University and OhioLINK.