Positional Cloning of the Mouse Circadian Gene

Abstract

We used positional cloning to identify the circadian Clock gene in mice. Clock is a large transcription unit with 24 exons spanning approximately 100,000 bp of DNA from which transcript classes of 7.5 and approximately 10 kb arise. Clock encodes a novel member of the bHLH-PAS family of transcription factors. In the Clock mutant allele, an A-->T nucleotide transversion in a splice donor site causes exon skipping and deletion of 51 amino acids in the CLOCK protein. Clock is a unique gene with known circadian function and with features predicting DNA binding, protein dimerization, and activation domains. CLOCK represents the second example of a PAS domain-containing clock protein (besides Drosophila PERIOD), which suggests that this motif may define an evolutionarily conserved feature of the circadian clock mechanism.

Circadian genes, rhythms and the biology of mood disorders

“…One reason to suspect that the manic-like phenotype seen in these mice may involve the circadian clock is that our laboratory has found that mice harboring a mutation in the CLOCK gene also display a behavioral profile that is strikingly similar to human mania (Roybal et al, in press). These mice have a point mutation in the CLOCK gene caused by ENU mutagenesis that results in a dominant-negative protein (King et al, 1997). Their behavioral profile includes hyperactivity in response to novelty and over the light/dark cycle, reduced depression-like behavior in the forced swim test and learned helplessness tests, reduced anxiety or increased risk taking behavior in several measures, and an increase in the reward value of cocaine, sucrose and intracranial self-stimulation (McClung et al, 2005;Roybal et al, in press).…”

The role of clock genes and rhythmicity in the liver

“…The hepatic oscillator is centered on a pair of transcriptional activators, BMAL1 (also named Mop3) (Bunger et al, 2000;Hogenesch et al, 1998) and CLOCK (Gekakis et al, 1998;King et al, 1997) and two classes of repressors of the Period (Per) Shearman et al, 1997;Sun et al, 1997;Tei et al, 1997) and Cryptochrome (Cry) gene families (Griffin et al, 1999;Kume et al, 1999;van der Horst et al, 1999;Vitaterna et al, 1999) (Fig. 2).…”

A mammalian ortholog of Drosophila timeless, highly expressed in SCN and retina, forms a complex with mPER1

“…Its expression pattern is similar to that of mPer1 mRNA (Sun et al 1997;Tei et al 1997), except that a smaller transcript was also detected in the liver. The expression of mTim mRNA that occurs in various tissues other than the brain, as with the other clock genes, mPer1, mPer2, mPer3, Clock and Bmal1 (MOP3) (Ikeda & Nomura 1997;King et al 1997;Shearman et al 1997;Sun et al 1997;Tei et al 1997;Takumi et al 1998a,b), suggests that tissue-specific local-oscillators may exist in the peripheral organs.…”