OUTPUTS

Cyanobacteria

Mechanisms in cyanobacteria regulated by the circadian clock include cell division and photosynthesis. A key mechanism controlled by circadian rhythms is the temporal separation of nitrogen fixing and photosynthesis as the former involves enzymes that are blocked by oxygen. The clock regulates the two systems so that nitrogen fixation occurs in the night when photosynthesis cannot occur. 

Some studies have shown that most of the genes in cyanobacteria are under circadian control (as shown by using randomly inserted promoterless luciferase genes and recording the bioluminescence) (Liu et al 1995). However this does not take into account the fact that bioluminescence is a manifestation of the end proteins. It does not necessarily correspond that the transcription of the genes is rhythmic. 

Neurospora

Only about 10% of genes in Neurospora are transcribed in a rhythmic manner (i.e. are clock controlled). However half of these genes cannot be induced by light or developmental signals (Bell-Pedersen et al 1996). The clock controlled genes regulate a number of different cellular systems including sugar metabolism, stress response and development (Harmer et al 2001).  

Drosophila

There are many clock controlled genes in Drosophila. Some of them feedback on the oscillator, some do not.

One clock controlled protein is the transcription factor VRILLE (VRI). This is expressed in the larval and adult brain (more specifically the ventrolateral neurons (LN_vs) from where the Drosophila clock is coordinated) (Blau and Young, 1999). Transcription of vri is regulated by dCLK and CYC.

Another gene involved in transmitting timing information from the oscillator is the gene pigment-dispersing factor (pdf). pdf is expressed in the LN_vs (Renn et al 2000). pdf is regulated by CYC and dCLK, as mutations in these genes cause a decrease in the levels of PDF. However the regulation is at the protein level as the transcription levels of pdf are steady. It is likely that PDF helps synchronise the clocks in different cells.

In Drosophila there is also a homologue to the mammalian protein CREB called dCREB2. dCREB2 has a 24 hour cycle. It is likely that dCREB2 has a similar function to CREB in mammals, in mediating behavioural responses to environmental cues (Belvin et al 1999).

Other clock genes do not feed back on the oscillator. These include takeout (to) which is involved in the control of feeding behaviour and lark, which is involved in fly eclosion (Harmer et al 2001). LARK is an RNA-binding protein that oscillates in the LN_vs, possibly doe to negative feedback by LARK (McNeil et al 1998).

Mammals

In mammals almost all tissues have their own circadian clock, each with its own output genes. Although the cycling genes constitute a small proportion of the total number of gene transcripts in the body, those that do cycle show a high degree of specificity (i.e. there is little overlap between tissue types).

In mammals, much of the transcription of output genes is mediated by mCLK and BMAL1 acting on E-boxes in the promoter regions of the genes. For example the leucine zipper transcription factor DBP is activated by mCLK binding to E-box motifs in the promoter of dbp (Ripperger et al 2000). DBP is expressed in the SCN, kidneys, liver, pancreas and heart (Harmer et al 2001). It regulates many different processes such as locomotor activity (animals deficient in this protein have shorter locomotor period times and are less active), sleep regulation (Franken et al 2000) and hormone regulation, through the transcription of genes such as cyp2a4 and cyp2a5 whose products catalyse one of the hydroxylation reactions in the metabolism of testosterone and estradiol (Lavery et al 1999).

Another from of control is through promoters containing CREs (see CREs and CREBs in Mammalian Inputs). Transcription of this type is found only in the SCN. As mentioned earlier, CREs are elements in the promoters of genes. Phosphorylated CREB transcription factors bind to the CREs initiating transcription. On of the processes regulated by CREs is the synthesis of melatonin. Phospho-CREBs initiate the synthesis of arylalkylamine N-acetyltransferase (AANAT) through the stimulation of cAMP released from the SCN (Harmer et al 2001).

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