Mammalian Cry1 and Cry2 are essential for maintenance of circadian rhythms

Abstract

Many biochemical, physiological and behavioural processes show circadian rhythms which are generated by an internal time-keeping mechanism referred to as the biological clock. According to rapidly developing models, the core oscillator driving this clock is composed of an autoregulatory transcription-(post) translation-based feedback loop involving a set of 'dock' genes. Molecular clocks do not oscillate with an exact 24-hour rhythmicity but are entrained to solar day/night rhythms by light. The mammalian proteins Cryl and Cry2, which are members of the family of plant blue-light receptors (cryptochromes) and photolyases, have been proposed as candidate light receptors for photoentrainment of the biological clock. Here we show that mice lacking the Cryl or Cry2 protein display accelerated and delayed free-running periodicity of locomotor activity, respectively. Strikingly, in the absence of both proteins, an instantaneous and complete loss of free-running rhythmicity is observed. This suggests that, in addition to a possible photoreceptor and antagonistic clock-adjusting function, both proteins are essential for the maintenance of circadian rhythmicity.

Differential roles for cryptochromes in the mammalian retinal clock

“…Wild-type (WT) C57BL/6J, Cry1 −/− , Cry2 −/− (20), and PER2::LUC (22) mice were used. Cry1 −/− and Cry2 −/− mice were maintained as homozygous lines.…”

“…Effects on non–image-forming responses to light in double-knockout mice were taken as evidence that CRYs functioned as photopigments (16–19). However, although Cry1 −/− ;Cry2 −/− double-knockout mice demonstrate negative masking, under constant conditions, these animals are arrhythmic (20). As such, altered responses in Cry1 −/− ;Cry2 −/− mice may be affected by loss of circadian gating of photic input.…”

Just-So Stories and Origin Myths: Phosphorylation and Structural Disorder in Circadian Clock Proteins

“…CRY1 and its paralog CRY2 cycle both in abundance and phosphorylation status, and the clock can run without either one, but not without both (van der Horst et al, 1999; Vitaterna et al, 1999). So they could make Cry1/Cry2 double-knockout cells whose clock would be completely dependent on whatever CRY they reintroduced.…”

Circadian Genes, xBmal1 and xNocturnin, Modulate the Timing and Differentiation of Somites in Xenopus laevis

“…The increase in mPer RNA is due to transcriptional activation by a heterodimer consisting of CLOCK and BMAL1 [17], [18], [19], [20], [21]. mPer 1–3 along with Cryptochromes ( Cry1 and Cry2 ) inhibit transcription activation by the CLOCK/BMAL1 heterodimer [22], [23]. This core transcription/translation feedback loop maintains, approximately, a 24 hour period as well as influencing the rhythmic expression of downstream targets called clock controlled genes (CCGs) [24], [25], [26].…”