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. (24th February 2013)

• Record Type: Journal Article
• Authors: Sayano, Tomoko; Kawakami, Yuriko; Kusada, Wataru; Suzuki, Takeshi; Kawano, Yuki; Watanabe, Akihiro; Takashima, Kana; Arimoto, Yashiho; Esaki, Kayoko; Wada, Akira; Yoshizawa, Fumiaki; Watanabe, Masahiko; Okamoto, Masahiro; Hirabayashi, Yoshio; Furuya, Shigeki
• Is Part Of: FEBS journal. Volume 280:Number 6(2013)
• Page Start: 1502
• Page End: 1517
• Publication Date: 2013-02-24
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.12146
• Languages: English
• ISSNs: 1742-464X

Abstract

<abstract abstract-type="main" id="febs12146-abs-0001"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Targeted disruption in mice of the gene encoding <sc>d</sc>‐3‐phosphoglycerate dehydrogenase (Phgdh) results in embryonic lethality associated with a striking reduction in free <sc>l</sc>‐serine and growth retardation including severe brain malformation. We previously observed a severe impairment in neurogenesis of the central nervous system of <italic>Phgdh</italic> knockout (KO) embryos and a reduction in the protein content of their brains. Although these findings suggest that <sc>l</sc>‐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 <italic>Eif4ebp1</italic> encoding eukaryotic initiation factor 4 binding protein 1 and its protein, 4E‐BP1, are markedly induced in the central nervous system of <italic>Phgdh </italic>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 <italic>Phgdh</italic> KO embryos. Induction of <italic>Eif4ebp1 </italic>mRNA and of 4E‐BP1 was reproduced in mouse embryonic fibroblasts established from <italic>Phgdh </italic>KO embryos under the condition of <sc>l</sc>‐serine deprivation. Induction of <italic>Eif4ebp1 </italic>mRNA was suppressed only when <sc>l</sc>‐serine was supplemented in the culture medium, indicating that reduced <sc>l</sc>‐serine availability regulates the induction of <italic>Eif4ebp1</italic>/4E‐BP1. These data suggest that elevated levels of 4E‐BP1 may be involved in a mechanism to arrest brain development in <italic>Phgdh </italic>KO embryos.</p> </abstract>