000117725 001__ 117725 000117725 005__ 20181203021112.0 000117725 0247_ $$2doi$$a10.1101/gad.301404 000117725 037__ $$aARTICLE 000117725 245__ $$aThe loss of circadian PAR bZip transcription factors results in epilepsy 000117725 269__ $$a2004 000117725 260__ $$c2004 000117725 336__ $$aJournal Articles 000117725 500__ $$aDepartment of Molecular Biology, National Center of Competence Research Frontiers in Genetics, Sciences III, University of Geneva, CH-1211 Geneva 4, Switzerland. 000117725 520__ $$aDBP (albumin D-site-binding protein), HLF (hepatic leukemia factor), and TEF (thyrotroph embryonic factor) are the three members of the PAR bZip (proline and acidic amino acid-rich basic leucine zipper) transcription factor family. All three of these transcriptional regulatory proteins accumulate with robust circadian rhythms in tissues with high amplitudes of clock gene expression, such as the suprachiasmatic nucleus (SCN) and the liver. However, they are expressed at nearly invariable levels in most brain regions, in which clock gene expression only cycles with low amplitude. Here we show that mice deficient for all three PAR bZip proteins are highly susceptible to generalized spontaneous and audiogenic epilepsies that frequently are lethal. Transcriptome profiling revealed pyridoxal kinase (Pdxk) as a target gene of PAR bZip proteins in both liver and brain. Pyridoxal kinase converts vitamin B6 derivatives into pyridoxal phosphate (PLP), the coenzyme of many enzymes involved in amino acid and neurotransmitter metabolism. PAR bZip-deficient mice show decreased brain levels of PLP, serotonin, and dopamine, and such changes have previously been reported to cause epilepsies in other systems. Hence, the expression of some clock-controlled genes, such as Pdxk, may have to remain within narrow limits in the brain. This could explain why the circadian oscillator has evolved to generate only low-amplitude cycles in most brain regions. 000117725 700__ $$aGachon, F. 000117725 700__ $$aFonjallaz, P. 000117725 700__ $$aDamiola, F. 000117725 700__ $$aGos, P. 000117725 700__ $$aKodama, T. 000117725 700__ $$aZakany, J. 000117725 700__ $$0240276$$aDuboule, D.$$g141236 000117725 700__ $$aPetit, B. 000117725 700__ $$aTafti, M. 000117725 700__ $$aSchibler, U. 000117725 773__ $$j18$$k12$$q1397-412$$tGenes Dev 000117725 909C0 $$0252099$$pUPDUB$$xU11705 000117725 909CO $$ooai:infoscience.tind.io:117725$$pSV$$particle 000117725 937__ $$aUPDUB-ARTICLE-2004-004 000117725 973__ $$aOTHER$$rREVIEWED$$sPUBLISHED 000117725 980__ $$aARTICLE