Functional properties of the suprachiasmatic nucleus : comparative analysis of the central pacemaker versus peripheral oscillators /
The generation of circadian rhythms in mammals is controlled by the hypothalamic suprachiasmatic nucleus (SCN). The central clock in the SCN mediates rhythmic processes throughout the body by regulating the oscillatory behavior of peripheral, "non-clock" tissues. In the present studies,...
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| Format: | Thesis Book |
| Language: | English |
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[Place of publication not identified] :
[publisher not identified] ;
2001.
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| Online Access: | http://proxy.library.tamu.edu/login?url=http://proquest.umi.com/pqdweb?did=726102531&sid=1&Fmt=2&clientId=2945&RQT=309&VName=PQD |
| Summary: | The generation of circadian rhythms in mammals is controlled by the hypothalamic suprachiasmatic nucleus (SCN). The central clock in the SCN mediates rhythmic processes throughout the body by regulating the oscillatory behavior of peripheral, "non-clock" tissues. In the present studies, the capacity to generate circadian oscillations endogenously and to confer this rhythmicity to other cells was compared in immortalized cells derived from the SCN and a fibroblast line to differentiate SCN pacemaker properties from the induced oscillatory behavior of non-clock tissues. To approach these issues, the functional properties of SCN2.2 and NIH/3T3 cells were examined using a novel coculture model which provided for a direct assessment of molecular and cellular indices of rhythmicity within these cells. Only SCN2.2 cells were capable of endogenously generating circadian rhythms in cellular metabolism and clock gene expression. Similar to SCN function in vivo, SCN2.2 cells imposed rhythms of metabolic activity and clock gene expression on cocultured fibroblasts via a diffusible signal. Although the identity of this diffusible messenger(s) is currently unknown, its generation and/or release from SCN2.2 cells appears to depend upon synchronous intercellular communication. Furthermore, studies using antisense oligonucleotides demonstrate that knockdown of CLOCK and PER2 levels in SCN2.2 cells alters metabolic rhythmicity in these cells and that CLOCK is involved in the generation and/or release of SCN2.2-derived output signals. Sustained metabolic rhythmicity in NIH/3T3 fibroblasts was dependent on continued exposure to SCN2.2-specific outputs. In contrast, a serum shock failed to drive metabolic rhythmicity in NIH/3T3 cells but induced high-amplitude oscillations in clock gene expression that displayed similar waveforms to that observed in the SCN in vivo. Despite these clock gene oscillations, serum-shocked NIH/3T3 cells failed to drive circadian rhythms in Per gene expression in cocultures of untreated fibroblasts. These findings suggest that only cells derived from the SCN contain the inherent functional properties required to serve as a circadian pacemaker and SCN-specific diffusible output signals are responsible for mediating the control of rhythmicity in non-clock cells types. Collectively, these results provide a foundation for future experiments in determining whether interactions between the molecular feedback loop and cellular metabolism play an important role in the mechanisms that control rhythmicity within both the SCN pacemaker and peripheral oscillators. |
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| Item Description: | Vita. "Major Subject: Medical Sciences". |
| Physical Description: | x, 164 leaves : illustrations ; 28 cm. Issued also on microfiche from University Microfilm Inc. |
| Bibliography: | Includes bibliographical references (leaves 139-163). |