The loss of circadian PAR bZip transcription factors results in epilepsy.

Department of Molecular Biology, National Center of Competence Research Frontiers in Genetics, Sciences III, University of Geneva, CH-1211 Geneva 4, Switzerland.
Genes & Development (Impact Factor: 12.44). 07/2004; 18(12):1397-412. DOI: 10.1101/gad.301404
Source: PubMed

ABSTRACT DBP (albumin D-site-binding protein), HLF (hepatic leukemia factor), and TEF (thyrotroph embryonic factor) are the three members of the PAR bZip (proline and acidic amino acid-rich basic leucine zipper) transcription factor family. All three of these transcriptional regulatory proteins accumulate with robust circadian rhythms in tissues with high amplitudes of clock gene expression, such as the suprachiasmatic nucleus (SCN) and the liver. However, they are expressed at nearly invariable levels in most brain regions, in which clock gene expression only cycles with low amplitude. Here we show that mice deficient for all three PAR bZip proteins are highly susceptible to generalized spontaneous and audiogenic epilepsies that frequently are lethal. Transcriptome profiling revealed pyridoxal kinase (Pdxk) as a target gene of PAR bZip proteins in both liver and brain. Pyridoxal kinase converts vitamin B6 derivatives into pyridoxal phosphate (PLP), the coenzyme of many enzymes involved in amino acid and neurotransmitter metabolism. PAR bZip-deficient mice show decreased brain levels of PLP, serotonin, and dopamine, and such changes have previously been reported to cause epilepsies in other systems. Hence, the expression of some clock-controlled genes, such as Pdxk, may have to remain within narrow limits in the brain. This could explain why the circadian oscillator has evolved to generate only low-amplitude cycles in most brain regions.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Circadian clocks orchestrate behavioral and physiological processes in a time-of-day dependent manner. The network of clock-controlled genes is intimately interconnected with metabolic regulatory circuits. Circadian clocks rhythmically regulate the expression and activity of key metabolic players, which in turn feed back on the circadian machinery on the transcriptional and post-transcriptional level. Mutations of clock genes are often associated with metabolic defects, especially in lipid and glucose metabolism. Accumulating data suggest that the reciprocal coordination of circadian and metabolic pathways is crucial for cellular homeostasis and the health of the organism.
    Cellular and Molecular Life Sciences CMLS 02/2014; · 5.62 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Studies on the molecular clockwork during aging have been hitherto addressed to core clock genes. These previous investigations indicate that circadian profiles of core clock gene expression at an advanced age are relatively preserved in the master circadian pacemaker, the hypothalamic suprachiasmatic nucleus (SCN), and relatively impaired in peripheral tissues. It remains to be clarified whether the effects of aging are confined to the primary loop of core clock genes, or also involve secondary clock loop components, including Rev-erbα and the clock-controlled genes Dbp and Dec1. Using quantitative real-time RT-PCR, we here report a comparative analysis of the circadian expression of canonical core clock genes (Per1, Per2, Cry1, Cry2,Clock and Bmal1) and non-core clock genes (Rev-erbα, Dbp and Dec1) in the SCN, liver, and heart of 3 month-old vs 22 month-old mice. The results indicate that circadian clock gene expression is significantly modified in the SCN and peripheral oscillators of aged mice. These changes are not only highly tissue-specific, but also involve different clock gene loops. In particular, we here report changes of secondary clock loop components in the SCN, changes of the primary clock loop in the liver, and minor changes of clock gene expression in the heart of aged mice. The present findings outline a track to further understanding the role of primary and secondary clock loop components and their crosstalk in the impairment of circadian output which characterizes aging.
    Experimental gerontology 01/2014; · 3.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Accumulating evidences indicate that circadian abnormalities lead to sleep disorder, neurodegenerative diseases and depression. We have reported that the polymorphisms of a clock-related gene, Tef, contributed to the risk of sleep disturbances and depression in the Parkinson disease. The objective of the present study was to examine whether the three clock genes we previously studied are associated with major depressive disorder (MDD) in the Chinese population. Methods 105 Subjects with MDD and 485 control subjects participated in this case-control study. Demographics, Mini-mental Status Examination (MMSE), and the Hamilton rating scale for depression (HAMD) were obtained in all subjects. Genotypes of single nucleotide polymorphisms (SNPs) of Cry1 rs2287161, Cry2 rs10838524 and Tef rs738499 were screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results MDD cases had a significantly higher frequency carrying the C allele and CC genotype in Cry1 rs2287161 and the T allele and TT genotype in Tef rs738499 than controls. Limitations The sample size of MDD group was relatively small. Conclusions The polymorphisms of Cry1 rs2287161 and Tef rs738499 are associated to MDD.
    Journal of affective disorders 01/2014; 157:100–103. · 3.76 Impact Factor

Full-text (2 Sources)

Available from
Jun 1, 2014