Assembling a Clock for All Seasons: Are There M and E Oscillators in the Genes?

Abstract

The hypothesis is advanced that the circadian pacemaker in the mammalian suprachiasmatic nucleus (SCN) is composed at the molecular level of a nonredundant double complex of circadian genes (per1, cry1, and per2, cry2). Each one of these sets would be sufficient for the maintenance of endogenous rhythmicity and thus constitute an oscillator. Each would have slightly different temporal dynamics and light responses. The per1/cry1 oscillator is accelerated by light and decelerated by darkness and thereby tracks dawn when day length changes. The per2 /cry2 oscillator is decelerated by light and accelerated by darkness and thereby tracks dusk. These M (morning) and E (evening) oscillators would give rise to the SCN's neuronal activity in an M and an E component. Suppression of behavioral activity by SCN activity in nocturnal mammals would give rise to adaptive tuning of the endogenous behavioral program to day length. The proposition-which is a specification of Pittendrigh and Daan's E-M oscillator model-yields specific nonintuitive predictions amenable to experimental testing in animals with mutations of circadian genes.

Effects of constant light on circadian rhythmicity in mice lacking functional cry genes: dissimilar from per mutants

“…The increasing values both in mCry1 ¡/¡ and mCry2 ¡/¡ with increasing LL light intensity refute the prediction concerning the mCry genes derived from the molecular two-component theory proposed by Daan et al (2001). Apparently neither mCry gene separately has to be functional for the lengthening of in response to continuous light.…”

“…While general in (diurnal) birds, this shortening of in response to constant light is unique among mammals, where so far all species measured exhibit an increase in circadian period in LL (AschoV 1979). The shortened in mPer2 Brdm1 mice in LL in two studies is a remarkable conWrmation of the deviant phenotype predicted by the molecular two-component model (Daan et al 2001). In our study there appeared to be no further shortening of the circadian cycle with increasing intensity beyond 1 lx in the mPer2 Brdm1 strain as was observed by Steinlechner et al (2002).…”

“…These results suggest that it may be worthwhile to collect more information on rhythmicity in LL in circadian gene mutants. In particular, a hypothesis on the response of 123 mPer1, mPer2, mCry1 and mCry2 to continuous light in subcomponents of the circadian oscillator yields speciWc predictions for the eVect of gene deletions in these responses (Daan et al 2001).…”

“…On the basis of known properties of the circadian system of mPer and mCry mutant mice, a molecular speciWcation of this hypothesis has been formulated by Daan et al (2001). This includes non-redundant roles for the mPer1 and mCry1 genes in the function of the M component, and for the mPer2 and the mCry2 genes in the E component.…”

“…Transcription of both sets of genes is activated by the CLOCK/BMAL1 protein dimer, and in turn negatively feeds back on the CLOCK/BMAL1 mediated transcription (e.g., King and Takahashi 2000;Shearman et al 2000;Kume et al 2004). According to the hypothesis by Daan et al (2001) the properties of the circadian system of mice with a deWcit in one of these genes should correspond with the properties of a circadian system with a deWcit in the E or M component. The results obtained by Steinlechner et al (2002) have conWrmed these predictions for mPer1 Brdm1 and mPer2 Brdm1 in constant light; the mCry1 and mCry2 mutant circadian properties in LL have not yet been studied.…”