title: Targeted disruption of the mouse 3-phosphoglycerate dehydrogenase gene causes severe neurodevelopmental defects and results in embryonic lethality.
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.
authors.affiliation: Neuronal Circuit Mechanisms Research Group, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yoshida
authors.forename: Shigeki
authors.initials: S
authors.lastname: Furuya
authors.forename: Soh
authors.initials: S
authors.lastname: Osuka
authors.forename: Junya
authors.initials: J
authors.lastname: Mitoma
authors.forename: Yoko
authors.initials: Y
authors.lastname: Shinoda
authors.forename: Masahiko
authors.initials: M
authors.lastname: Watanabe
authors.forename: Norihiro
authors.initials: N
authors.lastname: Azuma
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hashikawa
authors.forename: Shigeyoshi
authors.initials: S
authors.lastname: Itohara
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirabayashi
mesh_terms: D000483:Alleles; D000818:Animals; D015139:Blotting, Southern; D015153:Blotting, Western; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002237:Carbohydrate Dehydrogenases / Q000235:genetics* / Q000502:physiology*; D003600:Cytosol / Q000378:metabolism; D005091:Exons; D006579:Heterozygote; D007150:Immunohistochemistry; D007438:Introns; D008099:Liver / Q000196:embryology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009154:Mutation; D009420:Nervous System / Q000196:embryology*; D010641:Phenotype; D050543:Phosphoglycerate Dehydrogenase; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D012694:Serine / Q000737:chemistry; D013234:Stem Cells; D013997:Time Factors
chemical_list: D012694:Serine; D002237:Carbohydrate Dehydrogenases; D050543:Phosphoglycerate Dehydrogenase