title: Inactivation of the 3-phosphoglycerate dehydrogenase gene in mice: changes in gene expression and associated regulatory networks resulting from serine deficiency.
abstract: D-3-Phosphoglycerate dehydrogenase (Phgdh) is a necessary enzyme for de novo L-serine biosynthesis. Mutations in the human PHGDH cause serine deficiency disorders characterized by severe neurological symptoms including congenital microcephaly and psychomotor retardation. We showed previously that targeted disruption of Phgdh in mice causes overall growth retardation with severe brain microcephaly and leads to embryonic lethality. Here, amino acid analysis of Phgdh knockout (KO) mouse embryos demonstrates that free serine and glycine concentrations are decreased markedly in head samples, reflecting the metabolic changes of serine deficiency found in human patients. To understand the pathogenesis of serine deficiency disorders at the molecular level, we have exploited this animal model to identify altered gene expression patterns using a microarray technology. Comparative microarray analysis of the Phgdh KO and wild-type head at gestational day 13.5 revealed an upregulation of genes involved in transfer RNA aminoacylation, amino acid metabolism, amino acid transport, transcriptional regulation, and translation, and a downregulation of genes involved in transcription in neuronal progenitors and muscle and cartilage development. A computational network analysis software was used to construct transcriptional regulatory networks operative in the Phgdh KO embryos in vivo. These observations suggest that Phgdh inactivation alters transcriptional programs in several regulatory networks.
authors.affiliation: Laboratory of Metabolic Regulation Research, Kyushu University Bio-Architecture Center, Hakozaki, Fukuoka City, Fukuoka, Japan. shigekifur@brs.kyushu-u.ac.jp
authors.forename: Shigeki
authors.initials: S
authors.lastname: Furuya
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Yoshida
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Jyung Hoon
authors.initials: JH
authors.lastname: Yang
authors.forename: Tomoko
authors.initials: T
authors.lastname: Sayano
authors.forename: Norihiro
authors.initials: N
authors.lastname: Azuma
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Satoru
authors.initials: S
authors.lastname: Kuhara
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Hirabayashi
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods; D003433:Crosses, Genetic; D004622:Embryo, Mammalian; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D020411:Oligonucleotide Array Sequence Analysis; D050543:Phosphoglycerate Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D011506:Proteins / Q000032:analysis; D015203:Reproducibility of Results; D012694:Serine / Q000172:deficiency* / Q000235:genetics
chemical_list: D011506:Proteins; D012694:Serine; D050543:Phosphoglycerate Dehydrogenase