L-serine deficiency caused by genetic Phgdh deletion leads to robust induction of 4E-BP1 and subsequent repression of translation initiation in the developing central nervous system.
Targeted disruption in mice of the gene encoding D-3-phosphoglycerate dehydrogenase (Phgdh) results in embryonic lethality associated with a striking reduction in free L-serine and growth retardation including severe brain malformation. We previously observed a severe impairment in neurogenesis of the central nervous system of Phgdh knockout (KO) embryos and a reduction in the protein content of their brains. Although these findings suggest that L-serine deficiency links attenuation of mRNA translation to severe developmental malformation of the central nervous system, the underlying key molecular event remains unexplored. Here we demonstrate that mRNA of Eif4ebp1 encoding eukaryotic initiation factor 4 binding protein 1 and its protein, 4E-BP1, are markedly induced in the central nervous system of Phgdh KO embryos, whereas a modest induction is observed in the liver. The increase in 4E-BP1 was associated with a decrease in the cap initiation complex in the brain, as shown by lower levels of eukaryotic translation initiation factor 4G bound to eukaryotic translation initiation factor 4E (eIF4E) and increased eIF4E interaction with 4E-BP1 based on 7-methyl-GTP chromatography. eIF4E protein and polysomes were also diminished in Phgdh KO embryos. Induction of Eif4ebp1 mRNA and of 4E-BP1 was reproduced in mouse embryonic fibroblasts established from Phgdh KO embryos under the condition of L-serine deprivation. Induction of Eif4ebp1 mRNA was suppressed only when L-serine was supplemented in the culture medium, indicating that reduced L-serine availability regulates the induction of Eif4ebp1/4E-BP1. These data suggest that elevated levels of 4E-BP1 may be involved in a mechanism to arrest brain development in Phgdh KO embryos.
Division of Systems Biology, Department of Bioscience and Biotechnology, Kyushu University, Fukuoka, Japan.
Tomoko
T
Sayano
Yuriko
Y
Kawakami
Wataru
W
Kusada
Takeshi
T
Suzuki
Yuki
Y
Kawano
Akihiro
A
Watanabe
Kana
K
Takashima
Yashiho
Y
Arimoto
Kayoko
K
Esaki
Akira
A
Wada
Fumiaki
F
Yoshizawa
Masahiko
M
Watanabe
Masahiro
M
Okamoto
Yoshio
Y
Hirabayashi
Shigeki
S
Furuya
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000196:embryology / Q000378:metabolism / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins; D003470:Culture Media / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D047108:Embryonic Development; D039603:Eukaryotic Initiation Factor-4G / Q000235:genetics / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D010442:Peptide Chain Initiation, Translational; D050543:Phosphoglycerate Dehydrogenase / Q000235:genetics*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011132:Polyribosomes / Q000235:genetics / Q000378:metabolism; D025941:Protein Interaction Mapping; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D003470:Culture Media; C499527:Eif4ebp1 protein, mouse; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; C497762:Notch1 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D051881:Receptor, Notch1; D012097:Repressor Proteins; D012694:Serine; D050543:Phosphoglycerate Dehydrogenase