CLOCK GENES IN

MAMMALS

 

In mammals, the biological clock is controlled from the suprachaismatic nucleus (SCN), an area of the brain in the hypothalamus. In addition, clock genes are found expressed all over the body often these clocks behave differently from the one in the SCN although it is the SCN that coordinates and regulates these peripheral clocks. Unless stated differently, the clock in this chapter refers to the SCN clock.

On the surface, the mammalian clock (here represented by the mouse) is remarkably similar to the one found in Drosophila, with apparently many of the same genes. There are 3 period genes (mper1, mper2 and mper3), a timeless homologue (mtim), a gene similar to clock (mclk) and a gene homologous to cycle called either mop3 or bmal1. (Harmer 2001). However there are a lot of differences between the Drosophila clock and the mouse clock. 

As in Drosophila, mclk and bmal1 (the cyc homologue) are transcription factors that contain a bHLH motif and a PAS domain, and like Drosophila these genes act as positive elements in the clock. This is where the similarity ends. In mice bmal1 cycles, with peak levels of both mRNA and BMAL1 protein occurring in the middle of the night (Shearman et al 2000). mclk on the other hand does not cycle (Dunlap 1999) (compare this with the actions of cyc and dclk). It may be therefore that the oscillator in mice is bmal1, where as in Drosophila it is dclk. mclk and bmal1 drive the expression of the other mouse clock genes (Shearman et al 2000), hence why they are the positive elements. 

It is the negative feedback where things get interesting. There are 3 period genes in mice called mper1, mper2 and mper3. All of these have cyclic transcription and protein patterns (Zylka 1998). These genes peak together in the SCN at the end of the day (Kume et al 1999).  

The mper genes may have a role to play in the adaptation of mammals to changing photoperiods. Each protein reacts in a different was to a light stimulus, with mper1 being induced quickly, mper2 being induced more slowly (after 2-3 hours) and mper3 not being light responsive. This may have a role in explaining phase shifts in response to light.  

In Drosophila, PER has an antagonistic effect on CYC and dCLK. In mice, all 3 mPER proteins also act on mCLK and BMAL1 and have an antagonistic effect on the activation of these genes. However this action is not as strong as the inhibition seen in Drosophila (Kume et al 1999). 

As stated at the beginning of this chapter, it was stated that mice contain a homologue of the Drosophila gene timeless (tim). However there is no evidence that mtim has any role in the mammalian circadian rhythm. An mtim knockout mouse shows no altered circadian rhythm (Gotter et al 2000). In addition there is no association between the mPER and mTIM proteins as there is with the Drosophila versions. 

Negative feedback may also be supplied by the cryptochromes mCRY1 and mCRY2. In both Drosophila and many plants, cryptochromes act as blue light photoreceptors, transmitting information about light to the circadian clock (Sancar 2000). However light detecting ability has not yet been shown in mCRY1 and mCRY2 (Harmer 2001). mCRY1 and mCRY2 are rhythmically expressed nuclear proteins. These interact with each of the mPER proteins, translocating each of them into the nucleus (Kume et al. 1999). 

Whilst the mPER proteins have a modest inhibitory effect on mCLK and BMAL1, it is thought that the mCRY proteins have a much stronger inhibitory effect. Both mCRY1 and mCRY2 prevent transcription of mclk and bmal1 by acting on the E-boxes of these genes. The interaction of the mCRY proteins with mPER2 may also help to stabilise it.

The Mammal clock. Proteins with positive actions are in yellow, negative components are in blue. Protein-protein interactions are indicated with dotted black arrows. Green arrows indicate a positive effect on some process or promoter, and red lines indicate an inhibitory action.  The mPERs and mCRYs positively regulate bmal1 transcription, possibly by inhibiting BMAL1/ mCLK, but evidence for this is inconclusive. The solid black lines indicate that the mCRYs stabilise or promote translation of mPER2 (Shearman et al).

(From Harmer et al 2001)

 

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