Embryonic Lethality in Mice Lacking Mismatch-Specific Thymine DNA Glycosylase Is Partially Prevented by DOPS, a Precursor of Noradrenaline

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  • Saito Yusuke
    Department of Cell Biology, Graduate School of Medicine, Tohoku University
  • Ono Tetsuya
    Department of Cell Biology, Graduate School of Medicine, Tohoku University
  • Takeda Naoki
    Center for Animal Resources and Development, Kumamoto University
  • Nohmi Takehiko
    Division of Genetics and Mutagenesis, National Institute of Health Sciences
  • Seki Masayuki
    Molecular Cell Biology Laboratory, Graduate School of Pharmaceutical Sciences, Tohoku University
  • Enomoto Takemi
    Molecular Cell Biology Laboratory, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University
  • Noda Tetsuo
    Genome Center, Japanese Foundation for Cancer Research
  • Uehara Yoshihiko
    Department of Cell Biology, Graduate School of Medicine, Tohoku University

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Abstract

Thymine DNA glycosylase (TDG) is involved in the repair of G:T and G:U mismatches caused by hydrolytic deamination of 5-methylcytosine and cytosine, respectively. Recent studies have shown that TDG not only has G-T/U glycosylase activities but also acts in the maintaining proper epigenetic status. In order to investigate the function of TDG in vivo, mice lacking Tdg, Tdg (−/−), were generated. Tdg mutant mice died in utero by 11.5 days post coitum (dpc), although there were no significant differences in the spontaneous mutant frequencies between wild type and Tdg (−/−) embryos. On the other hand, the levels of noradrenaline in 10.5 dpc whole embryos, which is necessary for normal embryogenesis, were dramatically reduced in Tdg (−/−) embryos. Consequently, we tested the effect of D, L-threo-3, 4-dihydroxyphenylserine (DOPS), a synthetic precursor of noradrenaline, on the survival of the Tdg (−/−) embryos. DOPS was given to pregnant Tdg (+/−) mice from 6.5 dpc through drinking water. Most of the Tdg (−/−) embryos were alive at 11.5 dpc, and they were partially rescued up to 14.5 dpc by the administration of DOPS. In contrast, the administration of L-3, 4-dihydroxyphenylalanine (L-DOPA) had marginal effects on Tdg (−/−) embryonic lethality. No embryo was alive without DOPS beyond 11.5 dpc, suggesting that the lethality in (−/−) embryos is partially due to the reduction of noradrenaline. These results suggest that embryonic lethality in Tdg (−/−) embryos is due, in part, to the reduction of noradrenaline levels.

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