Impaired neurogenesis in embryonic spinal cord of Phgdh knockout mice, a serine deficiency disorder model

Kawakami, Yuriko; Yoshida, Kazuyuki; Yang, Jung Hoon; Suzuki, Takeshi; Azuma, Norihiro; Sakai, Kazuhisa; Hashikawa, Tsutomu; Watanabe, Masahiko; Yasuda, Kaori; Kuhara, Satoru; Hirabayashi, Yoshio; Furuya, Shigeki

doi:10.1016/j.neures.2008.12.002

Cited by 26 publications

(18 citation statements)

References 36 publications

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“…Moreover, in these KO mice normal cell cycle progression and subsequent neurogenesis involving radial glia are severely impaired in the spinal cord. 15) As expected, all brain L-serine-derived lipids such as phosphatidylserine, phosphatidylethanolamine, sphingomyelin, and GD3 ganglioside are greatly reduced in Phgdh knockout mice. Of special note was the appearance of phosphatidylthreonine, which is barely detected with normal intracellular L-serine levels.…”

Section: L-serine Synthesis and Sphingolipids In The Brainsupporting

confidence: 72%

A world of sphingolipids and glycolipids in the brain —Novel functions of simple lipids modified with glucose—

Hirabayashi

2012

Proc. Jpn. Acad., Ser. B

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Glycosphingolipids (GSLs) are present on cell surface membranes and are particularly abundant in the brain. Since over 300–400 GSLs are synthesized from glucosylceramide (GlcCer), GlcCer is believed to only serve as the source of most GSLs, including sialic acid-containing GSLs or gangliosides, in the brain. Recent studies, however, suggest that GlcCer itself plays a role in the heat stress response, as it functions as a glucose donor for the synthesis of cholesterylglucoside, a lipid mediator in heat stress responses in animals. GlcCer in adipose tissues is also thought to be involved in mechanisms that regulate energy (sugar and lipid) metabolism. Our extensive structural study revealed an additional novel glucosylated membrane lipid, called phosphatidylglucoside, in developing rodent brains and human neutrophils. These lipids, all modified with glucose, are enriched in lipid rafts and play important roles in basic cellular processes. Here, I summarize the recent progress regarding these glucosylated lipids and their biosynthesis and regulation in the central nervous system (CNS).

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Section: L-serine Synthesis and Sphingolipids In The Brainsupporting

confidence: 72%

A world of sphingolipids and glycolipids in the brain —Novel functions of simple lipids modified with glucose—

Hirabayashi

2012

Proc. Jpn. Acad., Ser. B

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“…Data from our work and the work of others strongly suggest that an abundance of 4E‐BP1 may be involved in the mechanism to arrest growth of the CNS in Phgdh KO embryos. Although three isoforms of Eif4ebp ( Eif4ebp1 /4E‐BP1, Eif4ebp2 /4E‐BP2 and Eif4ebp3 /4E‐BP3) have been identified in mammals, our DNA microarray analyses demonstrated that only Eif4ebp1 was upregulated in Phgdh KO embryos . A trend toward increasing Eif4ebp1 mRNA levels was observed in the neonatal and adult hippocampus of brain‐specific Phgdh KO mice (Fig.…”

Section: Discussionmentioning

confidence: 71%

l‐Serine deficiency caused by genetic Phgdh deletion leads to robust induction of 4E‐BP1 and subsequent repression of translation initiation in the developing central nervous system

et al. 2013

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Targeted disruption in mice of the gene encoding D-3-phosphoglycerate dehydrogenase (Phgdh) results in embryonic lethality associated with a striking reduction in free L-serine and growth retardation including severe brain malformation. We previously observed a severe impairment in neurogenesis of the central nervous system of Phgdh knockout (KO) embryos and a reduction in the protein content of their brains. Although these findings suggest that L-serine deficiency links attenuation of mRNA translation to severe developmental malformation of the central nervous system, the underlying key molecular event remains unexplored. Here we demonstrate that mRNA of Eif4ebp1 encoding eukaryotic initiation factor 4 binding protein 1 and its protein, 4E-BP1, are markedly induced in the central nervous system of Phgdh KO embryos, whereas a modest induction is observed in the liver. The increase in 4E-BP1 was associated with a decrease in the cap initiation complex in the brain, as shown by lower levels of eukaryotic translation initiation factor 4G bound to eukaryotic translation initiation factor 4E (eIF4E) and increased eIF4E interaction with 4E-BP1 based on 7-methyl-GTP chromatography. eIF4E protein and polysomes were also diminished in Phgdh KO embryos. Induction of Eif4ebp1 mRNA and of 4E-BP1 was reproduced in mouse embryonic fibroblasts established from Phgdh KO embryos under the condition of L-serine deprivation. Induction of Eif4ebp1 mRNA was suppressed only when L-serine Abbreviations 3-PG, 3-phosphoglycerate; 4E-BP1, Eif4ebp1 protein; 7mGTP, 7-methyl-GTP; ActD, actinomycin D; CNS, central nervous system; eIF2a, a subunit of eukaryotic translation initiation factor 2; eIF4A, eukaryotic translation initiation factor 4A; eIF4E, eukaryotic translation initiation factor 4E; Eif4ebp1, eukaryotic initiation factor 4E binding protein 1; eIF4G, eukaryotic translation initiation factor 4G; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GCN2, general control nonderepressible 2 kinase; GLAST, astrocyte/radial glia-specific L-glutamate/L-aspartate transporter; HT, heterozygote; KO, knockout; MEF, mouse embryonic fibroblast; NMDA, N-methyl-D-aspartate; Phgdh, D-3-phosphoglycerate dehydrogenase; Psat, phosphoserine aminotransferase; Psph, phosphoserine phosphatase; QRT-PCR, quantitative real-time PCR; Shmt, serine hydroxymethyltransferase; WT, wild type.

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“…RNA was reverse transcribed to cDNA using the Qiagen Omniscript RT kit (Qiagen, Valencia, CA) following the manufacturer's instructions. qPCR was performed for quantification of ki-67 and β-actin mRNA on a Rotor-Gene 3000 (Corbett Research, Sydney, Australia) based on the published methods [20,21] . Changes in gene expression were determined using the ΔΔCt method [22] .…”

Section: Real-time Quantitative Polymerase Chain Reaction (Qpcr)mentioning

confidence: 99%

Sevoflurane exposure in 7-day-old rats affects neurogenesis, neurodegeneration and neurocognitive function

2012

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Objective Sevoflurane is widely used in pediatric anesthesia and former studies showed that it causes neurodegeneration in the developing brain. The present study was carried out to investigate the effects of sevoflurane on neurogenesis, neurodegeneration and behavior. Methods We administered 5-bromodeoxyuridine, an S-phase marker, before, during, and after 4 h of sevoflurane given to rats on postnatal day 7 to assess dentate gyrus progenitor proliferation and Fluoro-Jade staining for degeneration. Spatial reference memory was tested 2 and 6 weeks after anesthesia. Results Sevoflurane decreased progenitor proliferation and increased cell death until at least 4 days after anesthesia. Spatial reference memory was not affected at 2 weeks but was affected at 6 weeks after sevoflurane administration. Conclusion Sevoflurane reduces neurogenesis and increases the death of progenitor cells in developing brain. This might mediate the lateonset neurocognitive outcome after sevoflurane application.

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Impaired neurogenesis in embryonic spinal cord of Phgdh knockout mice, a serine deficiency disorder model

Cited by 26 publications

References 36 publications

A world of sphingolipids and glycolipids in the brain —Novel functions of simple lipids modified with glucose—

A world of sphingolipids and glycolipids in the brain —Novel functions of simple lipids modified with glucose—

l‐Serine deficiency caused by genetic Phgdh deletion leads to robust induction of 4E‐BP1 and subsequent repression of translation initiation in the developing central nervous system

Sevoflurane exposure in 7-day-old rats affects neurogenesis, neurodegeneration and neurocognitive function

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