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, Sep 30, 2015
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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.
    Frontiers in Systems Neuroscience 06/2014; 8:121. DOI:10.3389/fnsys.2014.00121
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    • "Similar to the E2A-PBX gene fusion, the N-terminal transactivation domains of E2A are joined to the basic leucine zipper dimerization domain of HLF. HLF is a member of the proline and acidic amino acid-rich basic leucine zipper (PAR bZip) transcription factor family and mice deficient in this protein develop without any cancer pathology (28). Both transactivation domains of E2A and the basic leucine zipper dimerization domain of HLF were required for transformation of NIH3T3 mouse fibroblasts (29). "
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    ABSTRACT: Leukemia remains the most common diagnosis in pediatric oncology and, despite dramatic progress in upfront therapy, is also the most common cause of cancer-related death in children. Much of the initial improvement in outcomes for acute lymphoblastic leukemia (ALL) was due to identification of cytotoxic agents that are active against leukemia followed by the recognition that combination of these cytotoxic agents and prolonged therapy are essential for cure. Recent data demonstrating lack of progress in patients for whom standard chemotherapy fails suggests that the ability to improve outcome for these children will not be dramatically impacted through more intensive or newer cytotoxic agents. Thus, much of the recent research focus has been in the area of improving our understanding of the genetics and the biology of leukemia. Although in vitro studies remain critical, given the complexity of a living system and the increasing recognition of the contribution of leukemia extrinsic factors such as the bone marrow microenvironment, in vivo models have provided important insights. The murine systems that are used can be broadly categorized into syngeneic models in which a murine leukemia can be studied in immunologically intact hosts and xenograft models where human leukemias are studied in highly immunocompromised murine hosts. Both of these systems have limitations such that neither can be used exclusively to study all aspects of leukemia biology and therapeutics for humans. This review will describe the various ALL model systems that have been developed as well as discuss the advantages and disadvantages inherent to these systems that make each particularly suitable for specific types of studies.
    Frontiers in Oncology 05/2014; 4:95. DOI:10.3389/fonc.2014.00095
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    • "Whereas Pdp1í µí¼€ is predominantly expressed in the nervous system, Pdp1í µí»¾ is predominantly expressed in the fat body [8]. The mammalian homologous factors DBP, TEF, and HLF also show a circadian rhythm in their expression/accumulation; their absence results in epilepsy [10]. Furthermore, these mammalian proteins have recently been linked to a mechanism of fatty acid regulation [11]. "
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    ABSTRACT: In exploring the utility of double-stranded RNA (dsRNA) injections for silencing the PAR-domain protein 1 (Pdp1) gene in adult Drosophila, we noticed a dramatic loss of fat tissue lipids. To verify that our RNAi approach produced the expected Pdp1 knockdown, the abdominal fat tissues sections were stained with PDP1 antibodies. PDP1 protein immunostaining was absent in flies injected with dsRNA targeting a sequence common to all known Pdp1 isoforms. Subsequent experiments revealed that lipid staining is reduced in flies injected with dsRNA against Pdp1 γ (fat body specific) and not against Pdp1 ε (predominantly involved in circadian mechanisms). Drosophila PDP1 γ protein shows a high homology to mammalian thyrotroph embryonic factor (TEF), albumin D site-binding protein (DBP), and hepatic leukemia factor (HLF) transcription factors. In an in vitro model of drug- (olanzapine-) induced adiposity in mouse 3T3-L1 cells, the mRNA content of HLF but not TEF and DBP was increased by the drug treatment. A knockdown of the HLF mRNA by transfecting the cultures with HLF dsRNA significantly reduced their lipid content. Furthermore, the HLF RNAi prevented olanzapine from increasing the cell lipid content. These results suggest that the PDP1/HLF system may play a role in physiological and drug-influenced lipid regulation.
    08/2013; 2013(22):297932. DOI:10.1155/2013/297932
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