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

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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.

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Acknowledgment

The authors thank staff members in the Division of Research Resources Center of RIKEN Brain Science Institute for technical assistance. This work was supported by Grants-in-Aid for Scientific Research Areas (C), no. 14580756 and (B) no. 18300125 to S.F. from the Japanese Ministry of Education, Culture, Sport, Science, and Technology.

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Authors and Affiliations

  1. Laboratory of Metabolic Regulation Research, Kyushu University Bio-Architecture Center, Hakozaki, Fukuoka City, Fukuoka, 812-8581, Japan

    Shigeki Furuya, Yuriko Kawakami, Jyung Hoon Yang & Tomoko Sayano

  2. Laboratory of Metabolic Architecture Design, Kyushu University Bio-Architecture Center, Fukuoka City, Fukuoka, Japan

    Satoru Kuhara

  3. Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka City, Fukuoka, Japan

    Shigeki Furuya, Yuriko Kawakami & Jyung Hoon Yang

  4. Graduate School of Systems Life Sciences, Kyushu University, Fukuoka City, Fukuoka, Japan

    Satoru Kuhara

  5. RIKEN Brain Science Institute, Wako, Saitama, 351-0198, Japan

    Shigeki Furuya, Kazuyuki Yoshida & Yoshio Hirabayashi

  6. Department of Applied Biochemistry, Utsunomiya University, Utsunomiya, 321-8505, Japan

    Kazuyuki Yoshida, Norihiro Azuma & Hideyuki Tanaka

  7. CREST, Japan Science and Technology Agency, Kawaguchi, 332-0012, Japan

    Yoshio Hirabayashi

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  1. Shigeki Furuya
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  2. Kazuyuki Yoshida
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  3. Yuriko Kawakami
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  4. Jyung Hoon Yang
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Correspondence to Shigeki Furuya.

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Furuya and Yoshida contributed equally to this work.

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Furuya, S., Yoshida, K., Kawakami, Y. et al. Inactivation of the 3-phosphoglycerate dehydrogenase gene in mice: changes in gene expression and associated regulatory networks resulting from serine deficiency. Funct Integr Genomics 8, 235–249 (2008). https://doi.org/10.1007/s10142-007-0072-5

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