Biomedical subjects

N Y Garceau

Publications and source records attributed to N Y Garceau.

5 recordsLinked to original sources

PubMed1997

Alternative initiation of translation and time-specific phosphorylation yield multiple forms of the essential clock protein FREQUENCY.

The frequency (frq) gene encodes central components of the transcription/translation-based negative-feedback loop comprising the core of the Neurospora circadian oscillator; posttranscriptional regulation associated with FRQ is surprisingly complex. Alternative use of translation initiation sites gives rise to two forms of FRQ whose levels peak 4-6 hr following the peak of frq transcript. Each form of FRQ is progressively phosphorylated over the course of the day, thus providing a number of temporally distinct FRQ products. The kinetics of these regulatory processes suggest a view of the clock where relatively rapid events involving translational regulation in the synthesis of FRQ and negative feedback of FRQ on frq transcript levels are followed by slower posttranslational regulation, ultimately driving the turnover of FRQ and reactivation of the frq gene.

Biological Clocks↗

PubMed1997

Thermally regulated translational control of FRQ mediates aspects of temperature responses in the neurospora circadian clock.

Two forms of FRQ, a central component of the Neurospora circadian clock, arise through alternative in-frame initiation of translation. Either form alone suffices for a functional clock at some temperatures, but both are always necessary for robust rhythmicity. Temperature regulates the ratio of FRQ forms by favoring different initiation codons at different temperatures; when either initiation codon is eliminated, the temperature range permissive for rhythmicity is demonstrably reduced. This temperature-influenced choice of translation-initiation site represents a novel adaptive mechanism that extends the physiological temperature range over which clocks function. Additionally, a temperature-dependent threshold level of FRQ is required to establish the feedback loop comprising the oscillator. These data may explain how temperature limits permissive for rhythmicity are established, thus providing a molecular understanding for a basic characteristic of circadian clocks.

Biological Clocks↗

PubMed1997

Dissection of a circadian oscillation into discrete domains.

The circadian oscillator in Neurospora is a negative feedback loop involving as principal players the products of the frequency (frq) locus. frq encodes multiple forms of its protein product FRQ, which act to depress the amounts of frq transcript. In this scheme there are two discrete and separable steps to the circadian cycle, negative feedback itself (repression) in which FRQ acts to decrease the levels of its own transcript, and recovery from repression (derepression) in which frq transcript levels return to peak amounts. By introducing an exogenously regulatable frq transgene into a frq loss-of-function strain (frq9), we created an artificial system in which the two separate steps in the circadian cycle can be initiated and followed separately for purposes of observing their kinetics. Under these conditions the frq-FRQ cycle occupies the time scale of a full circadian cycle. During this time, the process of negative feedback of FRQ on frq transcript levels is rapid and efficient; it requires only 3 to 6 h and can be mediated by on the order of 10 molecules of FRQ per nucleus, a level even less than that seen in the normal oscillation. In contrast, recovery from negative feedback requires 14 to 18 h, most of the circadian cycle, during which time de novo FRQ synthesis has stopped, and existing FRQ is progressively posttranslationally modified. Altogether the time required to complete both of these steps is in good agreement with the 22-h observed period length of the normal circadian cycle.

Circadian Rhythm↗

PubMed1995

The genetic basis of the circadian clock: identification of frq and FRQ as clock components in Neurospora.

Genetic approaches to the identification of clock components have succeeded in two model systems, Neurospora and Drosophila. In each organism, genes identified through screens for clock-affecting mutations (frq in Neurospora, per in Drosophila) have subsequently been shown to have characteristics of central clock components: (1) mutations in each gene can affect period length and temperature compensation, two canonical characteristics of circadian systems; (2) each gene regulates the timing of its own transcription in a circadian manner; and (3) in the case of frq, constitutively elevated expression will set the phase of the clock on release into normal conditions. Despite clear genetic and molecular similarities, however, the two genes are neither molecular nor temporal homologues. The timing of peak expression is distinct in the two genes, frq expression peaking after dawn and per expression peaking near midnight. Also, although expression of per from a constitutive promoter can rescue rhythmicity in a fly lacking the gene, constitutive expression of frq will not rescue rhythmicity in Neurospora frq-null strains, and in fact causes arrhythmicity when expressed in a wild-type strain. These data suggest that frq is and/or encodes a state variable of the circadian oscillator. Recent molecular genetic analyses of frq have shed light on the origin of temperature compensation and strongly suggest that this property is built into the oscillatory feedback loop rather than appended to it. It seems plausible that clocks are adjusted and reset through adjustments in central clock components such as frq, and, by extension, per.

Animals↗

PubMedDate not supplied

Circadian rhythms.

Circadian rhythms are a ubiquitous adaptation of eukaryotic organisms to the most reliable and predictable of environmental changes, the daily cycles of light and temperature. Prominent daily rhythms in behavior, physiology, hormone levels and biochemistry (including gene expression) are not merely responses to these environmental cycles, however, but embody the organism's ability to keep and tell time. At the core of circadian systems is a mysterious mechanism, located in the brain (actually the suprachiasmatic nucleus of the hypothalamus) of mammals, but present even in unicellular organisms, that functions as a clock. This clock drives circadian rhythms. It is independent of, but remains responsive to, environmental cycles (especially light). The interest in temporal regulation--its organization, mechanism and consequences--unites investigators in diverse disciplines studying otherwise disparate systems. This diversity is reflected in the brief reviews that summarize the presentations at a meeting on circadian rhythms held in New York City on October 31, 1992. The meeting was sponsored by the Fondation pour l'Etude du Système Nerveux (FESN) and followed a larger meeting held 18 months earlier in Geneva, whose proceedings have been published (M. Zatz (Ed.), Report of the Ninth FESN Study Group on 'Circadian Rhythms', Discussions in Neuroscience, Vol. VIII, Nos. 2 + 3, Elsevier, Amsterdam, 1992). Some speakers described progress made in the interim, while others addressed aspects of the field not previously covered.

Aging↗