BIO254:LightEntrainment

Introduction

The daily rhythm of life is maintained by a circadian clock which keeps organism with a capacity to make or coordinate a self-sustained circadian rhythm. The time kept by a circadian clock enables the organism to respond physiologically and influences its behavior to daily environmental changes. Light entrainment means an organism's response to environmental light-dark transition cues that enables it to reset the clock. From some prokaryotes, fungi, plants and animals have been reported entrained by light triggering circadian pacemaker, which generates the oscillation and regulates various output rhythms. In such manner, an organism's physiology and behavior can be temporally regulated to occur.

Drosophila

How does circadian rhythm be regulated in Drosophila?

Drosophila serves as a good model for circadian clock research since many components share good conservations in other animals and it is the best-studied circadian feedback organism. The Drosophila circadian oscillator is composed of two intracellular feedback loops in gene expression: a PER/TIM loop and a CLK-CYC loop. CLK–CYC heterodimers bind to PER and TIM promoters and activate transcription of both PER and TIM. The DBT and Shaggy/GSK3 protein kinases regulate PER/TIM accumulation and nuclear transportation. TIM binds to phosphorylated PER-DBT and stabilizes the complex. PER is also stabilized by PP2a, which removes phosphates that were added to PER. The TIM–PER–DBT complexes are phosphorylated by Shaggy which, promotes their transport into the nucleus. TIM–PER–DBT complexes then bind to CLK–CYC, thereby removing CLK–CYC from the PER and TIM promoters and inhibiting PER and TIM transcription. In the nucleus, PER and TIM eventually dissociate, and PER is phosphorylated and degraded by DBT. Two more cycling transcription factors, Vrille and PDP1, form a second feedback loop by regulating transcription CLK and attributing the oscillation of PER/TIM loop.

Figure 1. Drosophila circadian clock (Image taken from S. Panda, 2002)

How could light alter the phase of the cycle?

• Light shifts the phase of the circadian oscillator, if a fly is transferred from a normal light-dark cycle to constant darkness. In Drosophila, mRNAs for TIM and PER are highest at the beginning of the night; TIM and PER proteins start to accumulate in the cytoplasm. In the middle of the night, as accumulation of PER-TIM-DBT complexes in the nucleus, CLK–CYC induced transcription was inhibited leading mRNAs of PER/TIM drop. Several photoreceptors are activated by light, and these photoreceptors then trigger the degradation of TIM via tyrosine phosphorylation. The light dependent degradation of TIM in the late night is accompanied by stable phase advances in the temporal regulation of the PER and TIM biochemical rhythms.

Figure 2. The immunocytochemistry assays on flies’ sections of heads with an anti-TIM antibody. (A)–(F) at the following times: ZT16 (A), ZT18 (B), ZT20 (C), ZT22 (D), ZT23.9 (E), and ZT1 (F). TIM expression is detectable in nuclei from ZT18 to ZT23.9. The western blot is Tim oscillation. (Image taken from M. Hunter-Ensor, 1996)

• A different link between light and central clock of Drosophila is cryptochrome (CRY) which is a blue-light sensitive pigment protein and plays a different role in the light entrainment. CRY transcription is influenced by other clock genes such as PER, TIM, CLK, and CYC. CRY protein levels are significantly affected by light exposure. Importantly, circadian photosensitivity is increased in a CRY-overexpressing strain. (Emery, 1998) It has been shown CRY binds to TIM in a light dependent way and causes fast degradation of TIM upon such binding, relieving its action as a transcriptional inhibitor. These physiological and genetic data link a specific photoreceptor molecule to circadian rhythm. CRY serves a major photoreceptor dedicated to the resetting of circadian rhythms in Drosophila.

Figure 3. Cry mutant was found abolishing the phase response curve to a brief pulse of light (Image taken from R. Stanewsky, 1998)

Mammal

How similar are fly’s circadian rhythm regulation and mammals’?

The light-responsive properties of the circadian pacemaker are conserved between flies and rodents. Are these timekeeping mechanisms conserved? Suprachiasmatic nucleus (SCN) have been shown the target of direct retinal projections and required for entrainment by light. The rhythm was eliminated when SCN was ablated. In mammals, a heterodimer, CLOCK and BMAL1, binds to the transcription promoters of PER and CRY, and activates their transcription. CKIε, homologue of Drosophia DBT, phosphorylates cytoplasmic PER and triggers its degradation. There are three different forms of PER (mPER1, mPER2, mPER3) and two different forms CRY proteins (mCRY1, mCRY2) in mammalians. The PER binds to CRY and CKIε to form a repression complex that translocates back into the nucleus. The complex interacts directly with CLOCK and BMAL1, and results in loss of their activation activity.

Figure 4. Mammalian circadian clock (Image taken from S. Panda, 2002)

Are different light entrainment mechanisms used in mammals?

Since mouse TIM does not show function similarly as in Drosophila to control rhythm and mouse cryptochromes (mCRY1 and mCRY2) have no distinct role in being photoreceptors for entrainment, mammals likely use different mechanisms of light entrainment. Eye loss in mammals abolishes light entrainment, indicating that the eyes provide the major source of light information to the clock pacemakers. Mice without both rods and cones photoreceptors are blind, but they still retain many eye-mediated responses to light. Retinal ganglion cells express melanopsin, a photo pigment that confers this photosensitivity. However, the melanopsin deficient mutants only show attenuation of circadian rhythm. Recently, the study done by S. Panda et al. showed that outer-retinal degeneration with a deficiency in melanopsin mutant exhibits complete loss of light entrainment of the circadian oscillator. We can conclude that both the unique characteristics of melanopsin and photoreceptor cell type provide integrated inputs to SCN for light entrainment

Figure 5 Photoinhibition levels by extension of light into the anticipated dark phase. It shows either the melanopsin-containing or the classical outer-retinal photoreceptors are sufficient for transducing photic information to critical brain areas. (Image taken from S. Panda, 2006)

References

1.S. Panda, J.B. Hogenesch and S.A. Kay, Nature, 2002, 417,329-335

2.Emery, P., So, W. V., Kaneko, M., Hall, Cell, 1998, 95(5), 669-79

3.R. Stanewsky, M. Kaneko, P. Emery, B. Beretta, K. Wager-Smith, S. A. Kay, M. Rosbash, J. C. Hall , Cell, 1998, 95(5), 681-79

4.M. Hunter-Ensor, A. Ousley, and A. Sehgal, Cell, 1996, 84, 677–685

5.R. G. Foster, Neuron, 1998, 20, 829

6.M.S. Freedman, R.J. Lucas,B. Soni, M. von Schantz, M. Muñoz, Z. David-Gray, R. Foster, Science, 1999, 284, 5413, 502 – 504

7.S. Panda, I. Provencio, D. C. Tu, S.S. Pires, M.D. Rollag, A.M. Castrucci, M.T. Pletcher, T.K. Sato, T. Wiltshire, M. Andahazy, S.A. Kay, R.N. Van Gelder, J.B. Hogenesch, Science, 2006, 301, 525-527

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