Gachon, F. et al. The loss of circadian PAR bZip transcription factors results in epilepsy. Genes Dev. 18, 1397-1412

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: 10.8). 07/2004; 18(12):1397-412. DOI: 10.1101/gad.301404
Source: PubMed


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.

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Available from: Francesca Damiola
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    • "Namely, core clock cogwheels were considered so since their mutation or inactivation leads to obvious defects in circadian behavior (reviewed in[11]). Oppositely, the output effectors do not play a role in the ticking of the molecular oscillator but participate in regulation of gene expression in various physiological processes, as exemplified by the transcription factors of the PARbZip family[12,13]or KLF15[14,15]. In contrast to these transcriptional regulators, Usp2 encodes the well conserved deubiquitylating enzyme (DUB) USP2 that is involved in post-translational regulation of protein function and stability by Ubiquitin (Ub) and its relatives the Ubiquitin-like (Ub-like) proteins SUMO, NEDD8 and ISG1516171819. "
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    ABSTRACT: The mammalian circadian clock influences most aspects of physiology and behavior through the transcriptional control of a wide variety of genes, mostly in a tissue-specific manner. About 20 clock-controlled genes (CCGs) oscillate in virtually all mammalian tissues and are generally considered as core clock components. One of them is Ubiquitin-Specific Protease 2 (Usp2), whose status remains controversial, as it may be a cogwheel regulating the stability or activity of core cogwheels or an output effector. We report here that Usp2 is a clock output effector related to bodily Ca2+ homeostasis, a feature that is conserved across evolution. Drosophila with a whole-body knockdown of the orthologue of Usp2, CG14619 (dUsp2-kd), predominantly die during pupation but are rescued by dietary Ca2+ supplementation. Usp2-KO mice show hyperabsorption of dietary Ca2+ in small intestine, likely due to strong overexpression of the membrane scaffold protein NHERF4, a regulator of the Ca2+ channel TRPV6 mediating dietary Ca2+ uptake. In this tissue, USP2-45 is found in membrane fractions and negatively regulates NHERF4 protein abundance in a rhythmic manner at the protein level. In clock mutant animals (Cry1/Cry2-dKO), rhythmic USP2-45 expression is lost, as well as the one of NHERF4, confirming the inverse relationship between USP2-45 and NHERF4 protein levels. Finally, USP2-45 interacts in vitro with NHERF4 and endogenous Clathrin Heavy Chain. Taken together these data prompt us to define USP2-45 as the first clock output effector acting at the post-translational level at cell membranes and possibly regulating membrane permeability of Ca2+.
    Full-text · Article · Jan 2016 · PLoS ONE
    • "Mice lacking 1 or 2 of these factors have mild phenotypes that may be due to the fact that DBP, TEF, and HLF have well-conserved amino acid sequences and thus they likely compensate for each other in the single or double KO mice. Mice lacking all 3 usually do not live longer than 1 year, with symptoms such as seizures occurring during the first 3 months of life (Gachon et al., 2004). In the kidney of the triple KO mice, Northern blot analysis revealed significantly less mRNA from potential target genes involved in detoxification and drug metabolism. "
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    ABSTRACT: Since the kidney is integral to maintenance of fluid and ion homeostasis, and therefore blood pressure regulation, its proper function is paramount. Circadian fluctuations in blood pressure, renal blood flow, glomerular filtration rate, and sodium and water excretion have been documented for decades, if not longer. Recent studies on the role of circadian clock proteins in the regulation of a variety of renal transport genes suggest that the molecular clock in the kidney controls circadian fluctuations in renal function. The circadian clock appears to be a critical regulator of renal function with important implications for the treatment of renal pathologies, which include chronic kidney disease and hypertension. The development, regulation, and mechanism of the kidney clock are reviewed here.
    No preview · Article · Nov 2015 · Journal of Biological Rhythms
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    • "Spontaneous electrographic seizures were documented in mice lacking Pten, a tumor suppressor gene that also significantly affects free-running rhythm (Ogawa et al., 2007). Deletion of three distinct PAR bZip transcription factors, proteins that accumulate with strong diurnal rhythms in critical brain areas such as the suprachiasmatic nucleus of the hypothalamus, causes spontaneous seizures in mice and is associated with reduced threshold to audiogenic seizures (Gachon et al., 2004). Interestingly, interictal abnormalities, and occurrence of spontaneous behavioral seizures in triple knockout PAR bZip mice followed a circadian trend that paralleled the distribution of sleep. "
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    ABSTRACT: The epilepsies are a heterogeneous group of neurological diseases defined by the occurrence of unprovoked seizures which, in many cases, are correlated with diurnal rhythms. In order to gain insight into the biological mechanisms controlling this phenomenon, we characterized time-of-day effects on electrical seizure threshold in mice. Male C57BL/6J wild-type mice were maintained on a 14/10 h light/dark cycle, from birth until 6 weeks of age for seizure testing. Seizure thresholds were measured using a step-wise paradigm involving a single daily electrical stimulus. Results showed that the current required to elicit both generalized and maximal seizures was significantly higher in mice tested during the dark phase of the diurnal cycle compared to mice tested during the light phase. This rhythm was absent in BMAL1 knockout (KO) mice. BMAL1 KO also exhibited significantly reduced seizure thresholds at all times tested, compared to C57BL/6J mice. Results document a significant influence of time-of-day on electrical seizure threshold in mice and suggest that this effect is under the control of genes that are known to regulate circadian behaviors. Furthermore, low seizure thresholds in BMAL1 KO mice suggest that BMAL1 itself is directly involved in controlling neuronal excitability.
    Full-text · Article · Jun 2014 · Frontiers in Systems Neuroscience
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