The loss of circadian PAR bZip transcription factors results in epilepsy.
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.
Gachon
Frédéric
F
Department of Molecular Biology, National Center of Competence Research Frontiers in Genetics, Sciences III, University of Geneva, CH-1211 Geneva 4, Switzerland.
Fonjallaz
Philippe
P
Damiola
Francesca
F
Gos
Pascal
P
Kodama
Tohru
T
Zakany
Jozsef
J
Duboule
Denis
D
Petit
Brice
B
Tafti
Mehdi
M
Schibler
Ueli
U
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors; D001921:Brain / Q000378:metabolism; D002940:Circadian Rhythm; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004569:Electroencephalography; D004576:Electromyography; D004827:Epilepsy / Q000209:etiology*; D016326:Extracellular Matrix Proteins / Q000032:analysis / Q000172:deficiency* / Q000502:physiology*; D006023:Glycoproteins / Q000032:analysis / Q000172:deficiency* / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018377:Neurotransmitter Agents / Q000378:metabolism; D011731:Pyridoxal Kinase / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology
D050976:Basic-Leucine Zipper Transcription Factors; C485975:DBP protein, rat; D004268:DNA-Binding Proteins; C498260:Dbp protein, mouse; D016326:Extracellular Matrix Proteins; D006023:Glycoproteins; C490671:HLF protein, human; C490670:Hlf protein, mouse; D018377:Neurotransmitter Agents; C490748:Prelp protein, mouse; C490749:Prelp protein, rat; D012333:RNA, Messenger; C489490:TEF protein, human; C489491:Tef protein, mouse; D014157:Transcription Factors; D011731:Pyridoxal Kinase