Oscillating on borrowed time: Diffusible signals from immortalized suprachiasmatic nucleus cells regulate circadian rhythmicity in cultured fibroblasts

Citation
G. Allen et al., Oscillating on borrowed time: Diffusible signals from immortalized suprachiasmatic nucleus cells regulate circadian rhythmicity in cultured fibroblasts, J NEUROSC, 21(20), 2001, pp. 7937-7943
Citations number
38
Categorie Soggetti
Neurosciences & Behavoir
Journal title
JOURNAL OF NEUROSCIENCE
ISSN journal
02706474 → ACNP
Volume
21
Issue
20
Year of publication
2001
Pages
7937 - 7943
Database
ISI
SICI code
0270-6474(20011015)21:20<7937:OOBTDS>2.0.ZU;2-5
Abstract
The capacity to generate circadian rhythms endogenously and to confer this rhythmicity to other cells was compared in immortalized cells derived from the suprachiasmatic nucleus (SCN) and a fibroblast line to differentiate SC N pacemaker properties from the oscillatory behavior of non-clock tissues. Only SCN2.2 cells were capable of endogenously generating circadian rhythms in 2-deoxyglucose uptake and Per gene expression. Similar to SCN function in vivo, SCN2.2 cells imposed rhythms of metabolic activity and Per gene ex pression on cocultured NIH/3T3 fibroblasts via a diffusible signal. The con ferred rhythms in NIH/3T3 cells were phase delayed by 4-12 hr relative to S CN2.2 circadian patterns, thus resembling the phase relationship between SC N and peripheral tissue rhythms in vivo. Sustained metabolic rhythmicity in NIH/3T3 cells was dependent on continued exposure to SCN2.2-specific outpu ts. In response to a serum shock the NIH/3T3 fibroblasts exhibited recurren t oscillations in clock gene expression, but not in metabolic activity. The se molecular rhythms in serum-shocked fibroblasts cycled in a phase relatio nship similar to that observed in the SCN in vivo; peak Per1 and Per2 mRNA expression preceded the rhythmic maxima in Cry1 and Cry2 mRNA levels by 4 h r. Despite these clock gene oscillations the serum-shocked NIH/3T3 cells fa iled to drive circadian rhythms of Per1 and Per2 expression in cocultures o f untreated fibroblasts, suggesting that expression and circadian regulatio n of the Per and Cry genes are not sufficient to confer pacemaker function. Therefore, SCN-specific outputs are necessary to drive circadian rhythms o f metabolic activity, and these output signals are not a direct product of clock gene oscillations.