Inactivation of the 3-phosphoglycerate dehydrogenase gene in mice: Changes in gene expression and associated regulatory networks resulting from serine deficiency

Shigeki Furuya, Kazuyuki Yoshida, Yuriko Kawakami, Jyung Hoon Yang, Tomoko Sayano, Norihiro Azuma, Hideyuki Tanaka, Satoru Kuhara, Yoshio Hirabayashi

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)235-249
Number of pages15
JournalFunctional and Integrative Genomics
Volume8
Issue number3
DOIs
Publication statusPublished - Aug 1 2008

Fingerprint

Phosphoglycerate Dehydrogenase
Serine
Gene Expression
Genes
Microcephaly
Amino Acids
Embryonic Structures
Transfer RNA Aminoacylation
Head
Muscle Development
Gene Regulatory Networks
Microarray Analysis
Knockout Mice
Glycine
Cartilage
Up-Regulation
Down-Regulation
Software
Animal Models
Technology

All Science Journal Classification (ASJC) codes

  • Genetics

Cite this

Inactivation of the 3-phosphoglycerate dehydrogenase gene in mice : Changes in gene expression and associated regulatory networks resulting from serine deficiency. / Furuya, Shigeki; Yoshida, Kazuyuki; Kawakami, Yuriko; Yang, Jyung Hoon; Sayano, Tomoko; Azuma, Norihiro; Tanaka, Hideyuki; Kuhara, Satoru; Hirabayashi, Yoshio.

In: Functional and Integrative Genomics, Vol. 8, No. 3, 01.08.2008, p. 235-249.

Research output: Contribution to journalArticle

Furuya, Shigeki ; Yoshida, Kazuyuki ; Kawakami, Yuriko ; Yang, Jyung Hoon ; Sayano, Tomoko ; Azuma, Norihiro ; Tanaka, Hideyuki ; Kuhara, Satoru ; Hirabayashi, Yoshio. / Inactivation of the 3-phosphoglycerate dehydrogenase gene in mice : Changes in gene expression and associated regulatory networks resulting from serine deficiency. In: Functional and Integrative Genomics. 2008 ; Vol. 8, No. 3. pp. 235-249.
@article{e444de1aad5f49e1a06422a5ad27b8c6,
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.",
author = "Shigeki Furuya and Kazuyuki Yoshida and Yuriko Kawakami and Yang, {Jyung Hoon} and Tomoko Sayano and Norihiro Azuma and Hideyuki Tanaka and Satoru Kuhara and Yoshio Hirabayashi",
year = "2008",
month = "8",
day = "1",
doi = "10.1007/s10142-007-0072-5",
language = "English",
volume = "8",
pages = "235--249",
journal = "Functional and Integrative Genomics",
issn = "1438-793X",
publisher = "Springer Verlag",
number = "3",

}

TY - JOUR

T1 - Inactivation of the 3-phosphoglycerate dehydrogenase gene in mice

T2 - Changes in gene expression and associated regulatory networks resulting from serine deficiency

AU - Furuya, Shigeki

AU - Yoshida, Kazuyuki

AU - Kawakami, Yuriko

AU - Yang, Jyung Hoon

AU - Sayano, Tomoko

AU - Azuma, Norihiro

AU - Tanaka, Hideyuki

AU - Kuhara, Satoru

AU - Hirabayashi, Yoshio

PY - 2008/8/1

Y1 - 2008/8/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=45449091548&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=45449091548&partnerID=8YFLogxK

U2 - 10.1007/s10142-007-0072-5

DO - 10.1007/s10142-007-0072-5

M3 - Article

C2 - 18228065

AN - SCOPUS:45449091548

VL - 8

SP - 235

EP - 249

JO - Functional and Integrative Genomics

JF - Functional and Integrative Genomics

SN - 1438-793X

IS - 3

ER -