Impaired neurogenesis in embryonic spinal cord of Phgdh knockout mice, a serine deficiency disorder model.
Mutations in the d-3-phosphoglycerate dehydrogenase (PHGDH; EC 1.1.1.95) gene, which encodes an enzyme involved in de novol-serine biosynthesis, are shown to cause human serine deficiency disorder. This disorder has been characterized by severe neurological symptoms including congenital microcephaly and psychomotor retardation. Our previous work demonstrated that targeted disruption of mouse Phgdh leads to a marked decrease in serine and glycine, severe growth retardation of the central nervous system, and lethality after embryonic day 13.5. To clarify how a serine deficiency causes neurodevelopmental defects, we characterized changes in metabolites, gene expression and morphological alterations in the spinal cord of Phgdh knockout mice. BeadChip microarray analysis revealed significant dysregulation of genes involved in the cell cycle. Ingenuity Pathway Analysis also revealed a significant perturbation of regulatory networks that operate in the cell cycle progression. Moreover, morphological examinations of the knockout spinal cord demonstrated a marked deficit in dorsal horn neurons. Radial glia cells, native neural stem/progenitor cells, accumulated in the dorsal ventricular zone, but they did not proceed to a G(0)-like quiescent state. The present integrative study provides in vivo evidence that normal cell cycle progression and subsequent neurogenesis of radial glia cells are severely impaired by serine deficiency.
Kawakami
Yuriko
Y
Laboratory of Metabolic Regulation Research, Kyushu University Bio-Architecture Center, Fukuoka 812-8581, Japan; Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Fukuoka 812-8581, Japan.
Yoshida
Kazuyuki
K
Yang
Jung Hoon
JH
Suzuki
Takeshi
T
Azuma
Norihiro
N
Sakai
Kazuhisa
K
Hashikawa
Tsutomu
T
Watanabe
Masahiko
M
Yasuda
Kaori
K
Kuhara
Satoru
S
Hirabayashi
Yoshio
Y
Furuya
Shigeki
S
D000818:Animals; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D053263:Gene Regulatory Networks / Q000235:genetics; D008659:Metabolic Diseases / Q000196:embryology / Q000235:genetics / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D050543:Phosphoglycerate Dehydrogenase / Q000172:deficiency / Q000235:genetics*; D012694:Serine / Q000172:deficiency*; D013116:Spinal Cord / Q000196:embryology / Q000473:pathology / Q000503:physiopathology; D014404:Tubulin / Q000378:metabolism
D027341:Excitatory Amino Acid Transporter 1; C493393:Slc1a3 protein, mouse; D014404:Tubulin; D012694:Serine; D050543:Phosphoglycerate Dehydrogenase