Psychiatry related information on Clk

• The Clock (Clk) mutation shortens circadian rhythms of locomotor activity and eclosion from ca. 24 h to 22.5-23 h [1].

High impact information on Clk

• This includes major components of the pacemaker program, as Clock also activates the rhythmic expression of cryptochrome, a gene that CLOCK normally represses [2].
• Coupled with an analysis of clock mutant (Clk) flies, a cell line designed to identify direct targets of the CLOCK (CLK) transcription factor and differential display, we uncovered several striking features of circadian gene networks [3].
• All oscillating gene expression is under clk control, indicating that Drosophila has no clk-independent circadian systems [3].
• The molecular circadian phenotype of homozygous cyc flies is like homozygous Clk flies presented in the accompanying paper: mutant flies have little or no transcription of the per and tim genes [4].
• The mutant phenotype results from a premature stop codon that eliminates much of the putative activation domain of this bHLH-PAS transcription factor, thus explaining the dominant features of Jrk [5].

Biological context of Clk

• However, whereas the transactivation domain in Drosophila lies in the C terminus of dCLOCK, in A. pernyi, it lies in the C terminus of apBMAL, which is highly conserved with the C termini of BMALs in other insects (except Drosophila) and in vertebrates [6].
• Mutations in clock genes in Drosophila melanogaster, period (per), timeless (tim), Clock (Clk), and cycle (cyc), produce multiple phenotypes associated with physiology, behavior, development, and morphology [7].
• Here, the Drosophila CLOCK protein was shown to induce transcription of the circadian rhythm genes period and timeless. dCLOCK functioned as a heterodimer with a Drosophila homolog of BMAL1 [8].
• The timeless promoter contains an 18-base pair element encompassing an E-box, which was sufficient to confer dCLOCK responsiveness to a reporter gene [8].
• Furthermore, a study examining the association between Clock gene polymorphisms and insomnia revealed a higher recurrence of initial, middle, and terminal insomnia in patients homozygous for the Clock genotype [9].

Anatomical context of Clk

• The blue light photoreceptor encoding cryptochrome (cry) gene is also a target for VRI repression, suggesting a broader role for VRI in the rhythmic repression of output genes that cycle in phase with Clk [10].
• Two additional studies support this role for PER: (1) Drosophila expressing PER that constitutively localizes to nuclei produce dominant behavioral arrhythmicity, and (2) constitutively nuclear PER represses dCLOCK/CYCLE-mediated transcription of per in cultured cells without TIM [11].

Associations of Clk with chemical compounds

• The Clock gene plays an essential role in the manifestation of circadian rhythms (approximately 24 h) in mice and is a member of the basic helix-loop-helix (bHLH) PER-ARNT-SIM (PAS) superfamily of transcription factors [12].

Regulatory relationships of Clk

• Within these feedback loops, CLK and CYCLE (CYC) activate per and tim transcription at the same time as they repress Clk transcription, thus controlling the opposite cycling phases of these transcripts [10].

Other interactions of Clk

• Per and Tim then associate, translocate to the nucleus, and repress the activity of Clk and Cyc [13].
• The Drosophila circadian oscillator consists of interlocked period (per)/timeless (tim) and Clock (Clk) transcriptional/translational feedback loops [10].
• In Drosophila, PDF functions in some of the neurons expressing the clock genes period, timeless, Clock, and cycle, and those clock genes in turn regulate pdf gene expression [14].

Analytical, diagnostic and therapeutic context of Clk

• As the upstream E-box was implicated in activation by dCLK/CYC in cell culture, we assayed sequences containing this E-box for association with proteins in fly head extracts [15].

References