Disease relevance of Clock

• The amount of milk secreted from dams, as calculated by the increase in pup body weight through suckling, was lower in Clock-mutant mothers vs. wild-type mice [1].
• We therefore showed that a Clock mutation attenuates obesity induced by a high-fat diet in mice with an ICR background through impaired dietary fat absorption [2].
• We found that homozygous Clock mutant mice have a greatly attenuated diurnal feeding rhythm, are hyperphagic and obese, and develop a metabolic syndrome of hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia [3].
• With the role of Clock and Bmal1 in fertility becoming clearer, it may be time to pursue the effect of polymorphisms in these genes in relation to the various types of infertility in humans [4].

Psychiatry related information on Clock

• Long-term, multielectrode recordings showed that heterozygous Clock mutant neurons have lengthened periods and that homozygous Clock neurons are arrhythmic, paralleling the effects on locomotor activity in the animal [5].
• The present results demonstrate that Clock mutation disrupts daily maternal behavior and the growth and survival rate of pups, especially with the breeding of more than 10 pups [1].
• The human Clock gene has been proposed as a possible candidate for disorders affected by alterations of circadian rhythm, including bipolar disorder and schizophrenia [6].
• These data indicate that the Clock mutation leads to increased exploratory behavior and increased escape-seeking behavior, and, conversely, does not result in increased anxiety or depressive-like behavior [7].
• The Clock mutation affected a number of sleep parameters during entrainment to a 12 hr light/dark (LD 12:12) cycle, when animals were free-running in constant darkness (DD), and during recovery from 6 hr of sleep deprivation in LD 12:12 [8].

High impact information on Clock

• The Clock mutation lengthens periodicity and reduces amplitude of circadian rhythms in mice [9].
• The effects of Clock are cell intrinsic and can be observed at the level of single neurons in the suprachiasmatic nucleus [9].
• Significantly, a number of intermediate phenotypes, including Clock/+ phenocopies and novel combinations of the parental behavioral characteristics, were seen in balanced chimeras [9].
• To address how cells of contrasting genotype functionally interact in vivo to control circadian behavior, we have analyzed a series of Clock mutant mouse aggregation chimeras [9].
• These results provide genetic evidence that MOP3 is the bona fide heterodimeric partner of mCLOCK [10].

Biological context of Clock

• NPAS2 is highly related in primary amino acid sequence to Clock, a transcription factor expressed in the suprachiasmatic nucleus that heterodimerizes with BMAL1 and regulates circadian rhythm [11].
• Rhythms of PER2::LUCIFERASE expression in suprachiasmatic nuclei explant cultures also are reduced in amplitude in Clock heterozygotes [12].
• Effects of altered Clock gene expression on the pacemaker properties of SCN2.2 cells and oscillatory properties of NIH/3T3 cells [13].
• Molecularly, the biological clock is based on the transcriptional/translational feedback loop of clock genes (mPer, mCry, Clock, and Bmal1) [14].
• The mouse Clock locus: sequence and comparative analysis of 204 kb from mouse chromosome 5 [15].

Anatomical context of Clock

• The expression of the Clock transcript is also developmentally regulated, but it is found principally in spermatogonia and spermatocytes up until the time of the first meiotic division [16].
• Per1 expression is not altered in testes from Clock mutant mice, suggesting that CLOCK does not activate Per1 in male germ cells, in contrast to what it does in other mouse tissues [16].
• To differentially examine the molecular elements necessary for the distinctive rhythm-generating and pacemaking properties of the SCN, the effects of antisense inhibition of Clock expression on the rhythms in 2-deoxyglucose uptake and Per gene expression were compared in immortalized SCN cells and a fibroblast cell line [13].
• OBJECTIVE: Clock genes are known to mediate circadian rhythms in the central nervous system and peripheral organs [17].
• These findings indicate that the Clock- and Cry-dependent molecular clock system is active in the salivary glands [18].

Associations of Clock with chemical compounds

• Nevertheless, the SCN of Clock(Delta19) + MEL mutant mice cannot maintain liver and muscle rhythmicity through rhythmic outputs, including melatonin secretion, in the absence of functional Clock expression in the tissues [19].
• Clock, a mammalian clock gene encoding a PAS-containing polypeptide, has now been cloned: it is likely that the Per homologues dimerize with other molecule(s) such as Clock through PAS-PAS interaction in the circadian clock system [20].
• Furthermore, a high-fat diet modulates carbohydrate metabolism by amplifying circadian variation in glucose tolerance and insulin sensitivity, and mutation of Clock restores the chow-fed phenotype [21].
• Gluconeogenesis is abolished by deletion of Bmal1 and is depressed in Clock mutants, but the counterregulatory response of corticosterone and glucagon to insulin-induced hypoglycaemia is retained [21].
• Regulation of dopaminergic transmission and cocaine reward by the Clock gene [22].

Regulatory relationships of Clock

• Involvement of circadian clock gene Clock in diabetes-induced circadian augmentation of plasminogen activator inhibitor-1 (PAI-1) expression in the mouse heart [23].

Other interactions of Clock

• The magnitude and time course of acute light induction in the suprachiasmatic nuclei of the only known light-induced core clock genes, Per1 and Per2, are not affected by the Clock/+ mutation [12].
• Similar to changes in molecular and physiological rhythmicity observed in the SCN of Clock mutant mice, the rhythmic pattern of Per2 expression was disrupted and the period of metabolic rhythmicity was increased in SCN2.2 cells subjected to antisense inhibition of Clock [13].
• Genetically linked to the molecular oscillator, it was identified as a repressor of the Bmal1 and Clock genes [24].
• Restricted feeding induces daily expression of clock genes and Pai-1 mRNA in the heart of Clock mutant mice [25].
• A robust attenuation of the Dec1 and Dec2 signals in Clock mutant mice was detected in all brain areas examined [26].

Analytical, diagnostic and therapeutic context of Clock

• To examine whether the CLOCK protein is required for the circadian expression of BMAL1 mRNA, in situ hybridization and Northern blot analysis were performed in the suprachiasmatic nucleus (SCN) and peripheral tissues of homozygous Clock mutant mice [27].
• Spontaneous discharges of individual neurons in the suprachiasmatic nucleus (SCN) of Clock mutant mice were recorded for over 5 days in organotypic slice cultures and dispersed cell cultures using a multi-electrode dish [28].
• Here, we show that transplantation of mouse fetal SCN tissue into the hypothalamus restores free-running circadian behavioral rhythmicity in Clock mutant or mCry1/mCry2 double knockout mice [29].
• Densitometry of immunolabeled brains indicated that the Clock mutation reduced AVP expression specifically in the SCN and not in other brain areas [30].

References