Targeted disruption of the mouse 3-phosphoglycerate dehydrogenase gene causes severe neurodevelopmental defects and results in embryonic lethality

J Biol Chem. 2004 Jan 30;279(5):3573-7. doi: 10.1074/jbc.C300507200. Epub 2003 Nov 26.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Blotting, Southern
  • Blotting, Western
  • Brain / embryology
  • Brain / metabolism
  • Carbohydrate Dehydrogenases / genetics*
  • Carbohydrate Dehydrogenases / physiology*
  • Cytosol / metabolism
  • Exons
  • Heterozygote
  • Immunohistochemistry
  • Introns
  • Liver / embryology
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Mutation
  • Nervous System / embryology*
  • Phenotype
  • Phosphoglycerate Dehydrogenase
  • Phosphorylation
  • Polymerase Chain Reaction
  • Serine / chemistry
  • Stem Cells
  • Time Factors

Substances

  • Serine
  • Carbohydrate Dehydrogenases
  • Phosphoglycerate Dehydrogenase