Targeted Disruption of the Mouse 3-Phosphoglycerate Dehydrogenase Gene Causes Severe Neurodevelopmental Defects and Results in Embryonic Lethality

Kazuyuki Yoshida, Shigeki Furuya, Soh Osuka, Junya Mitoma, Yoko Shinoda, Masahiko Watanabe, Norihiro Azuma, Hideyuki Tanaka, Tsutomu Hashikawa, Shigeyoshi Itohara, Yoshio Hirabayashi

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Abstract

D-3-Phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95) is the first committed enzyme Of L-serine biosynthesis in the phosphorylated pathway. To determine the physiological importance of Phgdh-dependent L-serine biosynthesis in vivo, we generated Phgdh-deficient mice using targeted gene disruption in embryonic stem cells. The absence of Phgdh led to a drastic reduction of L-serine metabolites such as phosphatidyl-L-serine and sphingolipids. Phgdh null embryos have small bodies with abnormalities in selected tissues and died after days post-coitum 13.5. Striking abnormalities were evident in the central nervous system in which the Phgdh null mutation culminated in hypoplasia of the telencephalon, diencephalon, and mesencephalon; in particular, the olfactory bulbs, ganglionic eminence, and cerebellum appeared as indistinct structures. These observations demonstrate that the Phgdh-dependent phosphorylated pathway is essential for normal embryonic development, especially for brain morphogenesis.

Original languageEnglish
Pages (from-to)3573-3577
Number of pages5
JournalJournal of Biological Chemistry
Volume279
Issue number5
DOIs
Publication statusPublished - Jan 30 2004
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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