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research article

The loss of circadian PAR bZip transcription factors results in epilepsy

Gachon, F.
•
Fonjallaz, P.
•
Damiola, F.
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2004
Genes & Development

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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Type
research article
DOI
10.1101/gad.301404
Author(s)
Gachon, F.
Fonjallaz, P.
Damiola, F.
Gos, P.
Kodama, T.
Zakany, J.
Duboule, D.  
Petit, B.
Tafti, M.
Schibler, U.
Date Issued

2004

Published in
Genes & Development
Volume

18

Issue

12

Start page

1397

End page

412

Note

Department of Molecular Biology, National Center of Competence Research Frontiers in Genetics, Sciences III, University of Geneva, CH-1211 Geneva 4, Switzerland.

Editorial or Peer reviewed

REVIEWED

Written at

OTHER

EPFL units
UPDUB  
Available on Infoscience
February 25, 2008
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/19238
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