Embryonic lethality in mice lacking mismatch-specific thymine DNA glycosylase is partially prevented by DOPS, a precursor of noradrenaline.
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.
Department of Cell Biology, Graduate School of Medicine, Tohoku University, Sendai, Japan.
Yusuke
Y
Saito
Tetsuya
T
Ono
Naoki
N
Takeda
Takehiko
T
Nohmi
Masayuki
M
Seki
Takemi
T
Enomoto
Tetsuo
T
Noda
Yoshihiko
Y
Uehara
D000818:Animals; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers / Q000235:genetics; D004298:Dopamine / Q000378:metabolism; D015103:Droxidopa / Q000378:metabolism* / Q000494:pharmacology; D004622:Embryo, Mammalian / Q000187:drug effects / Q000201:enzymology*; D044127:Epigenesis, Genetic / Q000235:genetics / Q000502:physiology*; D005260:Female; D007980:Levodopa / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009638:Norepinephrine / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044502:Thymine DNA Glycosylase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D007980:Levodopa; D044502:Thymine DNA Glycosylase; C113921:mismatch-specific thymine uracil-DNA glycosylase; D015103:Droxidopa; D004298:Dopamine; D009638:Norepinephrine