Targeted disruption of the mouse 3-phosphoglycerate dehydrogenase gene causes severe neurodevelopmental defects and results in embryonic lethality
Open accessAbstract
D-3-Phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95) is the first committed enzyme of L-serine biosynthesis in the phosphorylated pathway. To determine the physiological importance of Phgdh-dependent L-serine biosynthesis in vivo, we generated Phgdh-deficient mice using targeted gene disruption in embryonic stem cells. The absence of Phgdh led to a drastic reduction of L-serine metabolites such as phosphatidyl-L-serine and sphingolipids. Phgdh null embryos have small bodies with abnormalities in selected tissues and died after days post-coitum 13.5. Striking abnormalities were evident in the central nervous system in which the Phgdh null mutation culminated in hypoplasia of the telencephalon, diencephalon, and mesencephalon; in particular, the olfactory bulbs, ganglionic eminence, and cerebellum appeared as indistinct structures. These observations demonstrate that the Phgdh-dependent phosphorylated pathway is essential for normal embryonic development, especially for brain morphogenesis.
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Inhibitors of PHGDH might have a limited therapeutic index because de novo serine synthesis has an important physiological role in the central nervous system and PHGDH-deficient mice exhibit severe brain morphogenesis defects.
“However, inhibitors of PHGDH might have a limited therapeutic index, as de novo serine synthesis has an important physiological role in the central nervous system (Furuya, 2008) and PHGDH-deficient mice exhibit severe brain morphogenesis defects (Yoshida et al., 2004).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Yoshida et al., 2004
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One-Carbon Metabolism in Health and Disease
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“However, inhibitors of PHGDH might have a limited therapeutic index, as de novo serine synthesis has an important physiological role in the central nervous system (Furuya, 2008) and PHGDHdeficient mice exhibit severe brain morphogenesis defects (Yoshida et al., 2004).”
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“The simulation results are therefore consistent with hypertriglyceridemia resulting from LPL mutations, as previously demonstrated with the mouse knockout model [37-51].”
ResultAcuña‐Hidalgo, R., Schanze, D., Kariminejad, A., Nordgren, A., Kariminejad, M. H., Conner, P., Grigelioniené, G., Nilsson, D., Nordenskjöld, M., Wedell, A., et al. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.07.012 · Cited by 153 · see citing works
“We thus speculate that NLS is still not the ultimate end of the spectrum and that the most severe mutations leading to a complete defect of PSAT or PHGDHmight lead to a phenotype with very early prenatal lethality that has not yet been recognized; this is in line with the finding that mice with homozygous Phgdh knocko…”
ResultYang, J. H., Wada, A., Yoshida, K., Miyoshi, Y., Sayano, T., Esaki, K., Kinoshita, M. O., Tomonaga, S., Azuma, N., Watanabe, M., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.187443 · Cited by 147 · see citing works
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“This is not unexpected, given that, in the mouse Phgdh knockout model, complete enzyme deficiency is incompatible with life at the fetal stage.(14) Although the clinical presentation of patient 1 is very similar to that of patients with 3-phosphoglycerate dehydrogenase deficiency, there are some important differences.”
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“The phenotype was associated with embryonic lethality and clearly demonstrated the L-serine biosynthetic pathway was critical (Yoshida et al., 2004).”
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“Because complete disruption of de novo serine synthesis in Phgdh mice leads to severe defects in CNS development (70), it would be interesting to determine whether heterozygosity for Phgdh deficiency alters neuronal function or survival in models of MacTel or other CNS diseases.”
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de Koning, T. J. (2005) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-006-0269-0 · Cited by 73 · see citing works
“Indeed a 3-PGDH knockout mouse showed a phenotype consistent with a drastic reduction in proliferation of neuronal and glial precursor cells (Yoshida et al 2004).”
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“Furthermore, embryonic deletion of PHGDH in mice leads to hypoplasia of the telencephalon, diencephalon, mesencephalon, olfactory bulbs, ganglionic eminence, and cerebellum (121).”
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Amino acid synthesis deficiencies
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“The 3-PGDH knock out mouse published some years ago verymuch resembles the NLS phenotype and, so far, rescue of the severe developmental defects in mice with L-serine therapy has not been reported (Yoshida et al 2004).”
Stegen, S., Moermans, K., Stockmans, I., Thienpont, B., & Carmeliet, G. (2024) · Nature Metabolism · doi:10.1038/s42255-023-00948-y · Cited by 60 · see citing works
“Osteoclast-specific deletion of PHGDH was obtained by crossing Phgdh lox/lox mice (in which Phgdh exons 4 and 5 are flanked by LoxP sites 37 ) with lysozyme 2 gene promoter-Cre ( Lyz2 -Cre) transgenic mice 38 (resulting in Lyz2 -Cre + ; Phgdh lox/lox mice, referred to as Phgdh oc − mice).”
MethodO’Brien, L. L., Guo, Q., Bahrami‐Samani, E., Park, J., Hasso, S. M., Lee, Y.-J., Fang, A., Kim, A. D., Guo, J., Hong, T. M., et al. (2018) · PLoS Genetics · doi:10.1371/journal.pgen.1007181 · Cited by 55 · see citing works
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Blood triglyceride levels are associated with DNA methylation at the serine metabolism gene PHGDH
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On the phenotypic spectrum of serine biosynthesis defects
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Transporters at the Interface between Cytosolic and Mitochondrial Amino Acid Metabolism
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“Activity of serine synthesis is important for normal development, as deletion of Phgdh causes embryonic lethality in part due to neurological defects [95].”
BackgroundPHGDH is required for germinal center formation and is a therapeutic target in MYC-driven lymphoma
D’Avola, A., Legrave, N. M., Tajan, M., Chakravarty, P., Shearer, R. L., King, H. W., Kluckova, K., Cheung, E. C., Clear, A. J., Gunawan, A. S., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci153436 · Cited by 47 · see citing works
“Deletion of the first enzyme of SSP pathway, Phgdh, does not prevent development, but Phgdh-deficient mice are born with severe neurological defects and die soon after birth.(46) To overcome these limitations, we first crossed Eμ-Myc mice with Rosa26-CreERT2/+mice,(47) which express a tamoxifen-inducible Cre recombina…”
BackgroundAn essential role for de novo biosynthesis of L-serine in CNS development.
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“Both serine enantiomers are deeply related to neurophysiology; L-serine is a neurotrophic factor essential for brain morphogenesis (31, 32), whereas D-serine is a prerequisite for glutamatergic neurotransmission mediated by synaptic NMDA receptors (13, 18, 33–35).”
BackgroundKim, K. Y., Hwang, S., Park, S. Y., Kim, M. J., Jun, D. Y., & Kim, Y. H. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.07.018 · Cited by 46 · see citing works
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“Indeed, Phgdh knockout mice show decreased brain levels of serine-derived lipids, such as phosphatidylserine (PS), sphingomyelin, and ganglioside GD3 [3,4].”
BackgroundOne Carbon Metabolism and Mammalian Pregnancy Outcomes
Cai, S., Quan, S., Yang, G., Ye, Q., Chen, M., Yu, H., Wang, G., Wang, Y., Zeng, X., & Qiao, S. (2020) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.202000734 · Cited by 40 · see citing works
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De novo serine synthesis regulates chondrocyte proliferation during bone development and repair
Stegen, S., Loopmans, S., Stockmans, I., Moermans, K., Carmeliet, P., & Carmeliet, G. (2022) · Bone Research · doi:10.1038/s41413-021-00185-7 · Cited by 37 · see citing works
d-Serine: The right or wrong isoform?
Fuchs, S. A., Berger, R., & de Koning, T. J. (2011) · Brain Research · doi:10.1016/j.brainres.2011.05.039 · Cited by 36 · see citing works
Cancer's sweet tooth for serine
Luo, J. (2011) · Breast Cancer Research · doi:10.1186/bcr2932 · Cited by 36 · see citing works
“Similar central nervous system disorders have been observed in PHGDH knockout mice [6].”
PHGDH supports liver ceramide synthesis and sustains lipid homeostasis
Kang, Y. P., Falzone, A., Liu, M., González‐Sánchez, P., Choi, B.-H., Coloff, J. L., Saller, J. J., Karreth, F. A., & DeNicola, G. M. (2020) · Cancer & Metabolism · doi:10.1186/s40170-020-00212-x · Cited by 32 · see citing works
“Whole animal PHGDH deletion is embryonic lethal in mice as a consequence of overall developmental retardation and brain defects (Yoshida et al., 2004).”
BackgroundA Serine Synthesis Defect Presenting With a Charcot-Marie-Tooth–Like Polyneuropathy
Méneret, A., Wiame, E., Marelli, C., Lenglet, T., SCHAFTINGEN, E. V., & Sedel, F. (2012) · Archives of Neurology · doi:10.1001/archneurol.2011.1526 · Cited by 36 · see citing works
“play an essential role in the central nervous system.(1) Three enzymes”
BackgroundVitiello, D., Pinard, R., & Taylor, H. S. (2008) · Reproductive Sciences · doi:10.1177/1933719108316911 · Cited by 36 · see citing works
Yu, R. K., & Yanagisawa, M. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.04710.x · Cited by 36 · see citing works
“2005) or 3-phosphoglycerate dehydrogenase-KO mice (Yoshida et al. 2004), seems to”
BackgroundNakano, I., Dougherty, J. D., Kim, K., Klement, I., Geschwind, D. H., & Kornblum, H. I. (2007) · Stem Cells · doi:10.1634/stemcells.2007-0046 · Cited by 35 · see citing works
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Self-citationFuruya, S., Yoshida, K., Kawakami, Y., Yang, J. H., Sayano, T., Azuma, N., Tanaka, H., Kuhara, S., & Hirabayashi, Y. (2008) · Functional & Integrative Genomics · doi:10.1007/s10142-007-0072-5 · Cited by 30 · see citing works
“Our preliminary histological examinations suggested that differentiation of neurons was impaired in the Phgdh KO embryos ( Yoshida et al. 2004 ).”
BackgroundMethodResultInfluentialSelf-citationl-Serine induces sedative and hypnotic effects acting at GABAA receptors in neonatal chicks
Shigemi, K., Tsuneyoshi, Y., Hamasu, K., Li, H., Hayamizu, K., Denbow, D. M., & Furuse, M. (2008) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2008.09.036 · Cited by 28 · see citing works
“This idea is supported by the findings that neurons cannot maintain synthesis of serine-derived lipids without an external supply of L-serine (Mitoma et al., 1998b; Yoshida et al., 2004).”
BackgroundSerine and glycine physiology reversibly modulate retinal and peripheral nerve function
Lim, E. W., Fallon, R. J., Bates, C., Ideguchi, Y., Nagasaki, T., Handzlik, M. K., Joulia, E., Bonelli, R., Green, C. R., Ansell, B. R. E., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.07.021 · Cited by 27 · see citing works
Self-citationEffects of L-serine ingestion on human sleep
Ito, Y., Takahashi, S., Shen, M., Yamaguchi, K., & Satoh, M. (2014) · SpringerPlus · doi:10.1186/2193-1801-3-456 · Cited by 27 · see citing works
“In knockout mice in whom 3-phosphoglycerate dehydrogenase (PHGDH) in the L-serine synthetic pathway is inactivated, abnormal brain morphogenesis, including microcephaly and absence of specific regions, and brain dysfunction occurs (Yoshida et al. 1980).”
BackgroundBourque, D. K., Cloutier, M., Kernohan, K. D., Bareke, E., Grynspan, D., Michaud, J., & Boycott, K. M. (2019) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.61076 · Cited by 26 · see citing works
“One previous study has shown that murine knockout of Phgdh can lead to embryonic lethality (Yoshida et al., 2004).”
BackgroundTakeichi, T., Okuno, Y., Kawamoto, A., Inoue, T., Nagamoto, E., Murase, C., Shimizu, E., Tanaka, K., Kageshita, Y., Fukushima, S., et al. (2018) · Journal of Lipid Research · doi:10.1194/jlr.p087536 · Cited by 26 · see citing works
“An analysis of membrane lipid components in embryonic tissues of conventional Phgdh KO mice show that l-serine deficiency resulting from Phgdh deletion leads to a drastic reduction of major sphingolipids (15, 20).”
BackgroundIncreased mtDNA mutation frequency in oocytes causes epigenetic alterations and embryonic defects
Han, L., Chen, Y., Li, L., Ren, C., Wang, H., Wu, X., Ge, J., Shu, W., Chen, M., & Wang, Q. (2022) · National Science Review · doi:10.1093/nsr/nwac136 · Cited by 24 · see citing works
“These genes were selected based on their functions in embryogenesis and metabolism [34,35,37].”
BackgroundTippetts, T. S., Sieber, M., & Solmonson, A. (2023) · Development · doi:10.1242/dev.201610 · Cited by 24 · see citing works
Hathazi, D., Cox, D., D’Amico, A., Tasca, G. A., Charlton, R., Carlier, R., Baumann, J., Kollipara, L., Zahedi, R. P., Feldmann, I., et al. (2021) · Brain · doi:10.1093/brain/awab133 · Cited by 23 · see citing works
Ogawa, T., Ishida‐Kitagawa, N., Tanaka, A., Μatsumoto, T., Hirouchi, T., Akimaru, M., Tanihara, M., Yogo, K., & Takeya, T. (2006) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-006-0705-0 · Cited by 22 · see citing works
“In fact, when phgdh was deleted in mice, early embryonic lethality was observed, with multiple developmental defects, particularly in the central nervous system [24].”
BackgroundCan small molecular inhibitors that stop de novo serine synthesis be used in cancer treatment?
McNamee, M., Michod, D., & Niklison-Chirou, M. V. (2021) · Cell Death Discovery · doi:10.1038/s41420-021-00474-4 · Cited by 22 · see citing works
Oral administration of l-serine reduces the locomotor activity of socially isolated rats
Shigemi, K., Tsuneyoshi, Y., Yamada, S., Kabuki, Y., Hayamizu, K., Denbow, D. M., & Furuse, M. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.10.068 · Cited by 22 · see citing works
Chakraborty, S., Karmakar, A., Goswami, T., Ghosh, P., & Mandal, A. (2020) · Journal of Molecular Liquids · doi:10.1016/j.molliq.2020.114447 · Cited by 21 · see citing works
Zhou, Y., Hu, C., Zhao, X., Luo, P., Lu, J., Li, Q., Chen, M., Yan, D., Lu, X., Kong, H., et al. (2018) · Journal of Proteome Research · doi:10.1021/acs.jproteome.7b00866 · Cited by 21 · see citing works
Dietary serine supplementation: Friend or foe?
Jiang, J., Li, B., He, W., & Huang, C. (2021) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2021.08.011 · Cited by 20 · see citing works
The impact of amino acid metabolism on adult neurogenesis
Guo, Y., Luo, X., & Guo, W. (2023) · Biochemical Society Transactions · doi:10.1042/bst20220762 · Cited by 20 · see citing works
Stadhouders, L. E. M., Smith, J. A. B., Gabriel, B. M., Verbrugge, S. A. J., Hammersen, T. D., Kolijn, D., Vogel, I. S. P., Mohamed, A. D., de Wit, G. M. J., Offringa, C., et al. (2023) · Experimental Cell Research · doi:10.1016/j.yexcr.2023.113820 · Cited by 19 · see citing works
Deletion of PHGDH in adipocytes improves glucose intolerance in diet-induced obese mice
Okabe, K., Usui, I., Yaku, K., Hirabayashi, Y., Tobe, K., & Nakagawa, T. (2018) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2018.08.180 · Cited by 19 · see citing works
Self-citationJun, D. Y., Park, H. S., Lee, J. Y., Baek, J. Y., Park, H.-K., Fukui, K., & Kim, Y. H. (2008) · Gene · doi:10.1016/j.gene.2008.02.018 · Cited by 17 · see citing works
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Self-citationMitoma, J., Furuya, S., Shimizu, M., Shinoda, Y., Yoshida, K., Azuma, N., Tanaka, H., Suzuki, Y., & Hirabayashi, Y. (2004) · Gene · doi:10.1016/j.gene.2004.03.015 · Cited by 17 · see citing works
Self-citationSerine metabolism in aging and age-related diseases
Shan, S., & Hoffman, J. M. (2024) · GeroScience · doi:10.1007/s11357-024-01444-1 · Cited by 15 · see citing works
“In mice, the deletion of PHGDH, the first enzyme in the SSP, results in severe neurological defects and early postnatal death [121].”
Sayano, T., Kawano, Y., Kusada, W., Arimoto, Y., Esaki, K., Hamano, M., Udono, M., Katakura, Y., Ogawa, T., Kato, H., et al. (2016) · FEBS Open Bio · doi:10.1002/2211-5463.12038 · Cited by 15 · see citing works
Self-citationNovak, J. S. S., Polak, L., Baksh, S. C., Barrows, D., Schernthanner, M., Jackson, B. T., Thompson, E. A. N., Gola, A., Abdusselamoglu, M. D., Bonny, A. R., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.05.010 · Cited by 14 · see citing works
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“It must be mentioned that observations in PHGDH-deficient mice have been made that show abnormalities during embryonic development by malformations in the central nervous system [40].”
BackgroundHamano, M., Haraguchi, Y., Sayano, T., Zyao, C., Arimoto, Y., Kawano, Y., Moriyasu, K., Udono, M., Katakura, Y., Ogawa, T., et al. (2018) · FEBS Open Bio · doi:10.1002/2211-5463.12429 · Cited by 14 · see citing works
Self-citationPhosphoglycerate dehydrogenase positively regulates the proliferation of chicken muscle cells
Wang, H., Hu, M., Ding, Z., Zhou, X., Yang, S., Shen, Z., Yan, F., & Zhao, A. (2022) · Poultry Science · doi:10.1016/j.psj.2022.101805 · Cited by 13 · see citing works
“PHGDH catalyzes the first step in the synthesis of serine, a necessary precursor for the synthesis of various cell proliferation-related biomolecules (Yoshida et al., 2004).”
Backgroundl-Serine-O-phosphate in the central nervous system
Antflick, J. E., Vetiska, S., Baizer, J. S., Yao, Y., Baker, G. B., & Hampson, D. R. (2009) · Brain Research · doi:10.1016/j.brainres.2009.08.087 · Cited by 13 · see citing works
NAGAMACHI, S., Nishigawa, T., Takakura, M., Ikeda, H., Kodaira, M., Yamaguchi, T., Chowdhury, V. S., Yasuo, S., & Furuse, M. (2017) · Journal of Veterinary Medical Science · doi:10.1292/jvms.17-0577 · Cited by 13 · see citing works
“This pathway is essential for normal embryonic development, especially for brain morphogenesis [33].”
BackgroundProteomic Profiling of the Insoluble Pellets of the Transected Rat Spinal Cord
Yan, X., Liu, T., Yang, S., Ding, R. Q., Liu, Y., Zhang, X., Que, H., Wei, K., Luo, Z., & Liu, S. (2009) · Journal of Neurotrauma · doi:10.1089/neu.2008.0533 · Cited by 13 · see citing works
“Disruption of the PHGDH gene can cause severe neurodevelopmental defects (Yoshida et al., 2004).”
Shimizu, M., Furuya, S., Shinoda, Y., Mitoma, J., Okamura, T., Miyoshi, I., Kasai, N., Hirabayashi, Y., & Suzuki, Y. (2004) · Journal of Neuroscience Research · doi:10.1002/jnr.20102 · Cited by 13 · see citing works
“Targeted disruption of the mouse Phgdh gene culminated in embryonic lethality, accompanied by overall developmental retardation and striking defects of the brain (Yoshida et al., 2004).”
BackgroundSelf-citationHamano, M., Esaki, K., Moriyasu, K., Yasuda, T., Mohri, S., Tashiro, K., Hirabayashi, Y., & Furuya, S. (2021) · Nutrients · doi:10.3390/nu13103468 · Cited by 12 · see citing works
“L-Serine (Ser), a nutritionally dispensable amino acid, serves as an indispensable metabolite essential for mammalian fetal development [1,2].”
BackgroundSelf-citationKinoshita, M. O., Shinoda, Y., Sakai, K., Hashikawa, T., Watanabe, M., Machida, T., Hirabayashi, Y., & Furuya, S. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.02.001 · Cited by 12 · see citing works
Self-citationClinical histopathology and pathogenesis of macular telangiectasia type 2
Ntentakis, D. P., Ntentaki, A. M., Delavogia, E., Sakuno, G., Correa, V., Efstathiou, N. E., Aronow, M. E., Chew, E. Y., Miller, J. W., & Vavvas, D. G. (2025) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2025.101401 · Cited by 12 · see citing works
Phgdh serves a protective role in Il‑1β induced chondrocyte inflammation and oxidative‑stress damage
Huang, H., Liu, K., Ou, H., Qian, X., & Wan, J. (2021) · Molecular Medicine Reports · doi:10.3892/mmr.2021.12058 · Cited by 11 · see citing works
Jun, D. Y., Taub, D. D., Chrest, F. J., & Kim, Y. H. (2013) · Cellular Immunology · doi:10.1016/j.cellimm.2013.12.003 · Cited by 9 · see citing works
Jeon, G. S., Choi, D.-H., Lee, H. N., Kim, D. W., Chung, C. K., & Cho, S. S. (2008) · Neurochemical Research · doi:10.1007/s11064-008-9831-5 · Cited by 9 · see citing works
“Further, the targeted disruption of the Phgdh gene in mice resulted in embryonic lethality coupled with striking defects and retardation of brain development [34].”
Background
- Authors
- Yoshida, K., Furuya, S., Osuka, S., Mitoma, J., Shinoda, Y., Watanabe, M., Azuma, N., Tanaka, H., Hashikawa, T., Itohara, S., & Hirabayashi, Y.
- Affiliations
- RIKEN (JP)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Hokkaido University (JP)
- Utsunomiya University (JP)
- Corresponding author
- Furuya, Shigeki
- Hirabayashi, Yoshio
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-01
- Volume
- 279
- Issue
- 5
- Pages
- 3573-3577
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2097895708
- Cited by
- 161
- References
- 25
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 10 · 2023: 9 · 2022: 7 · 2021: 13 · 2020: 15 · 2019: 4 · 2018: 11 · 2017: 4 · 2016: 8 · 2015: 6 · 2014: 4 · 2013: 3 · 2012: 8
- FWCI
- 2.18
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- 3-phosphoglycerate dehydrogenase, PHGDH, L-serine biosynthesis, embryonic lethality, neurodevelopmental defects, brain morphogenesis, sphingolipids, olfactory bulb hypoplasia, ganglionic eminence, cerebellum, telencephalon, diencephalon, midbrain
- MeSH terms
- Alleles, Animals, Brain, Carbohydrate Dehydrogenases, Cytosol, Exons, Heterozygote, Immunohistochemistry, Introns, Liver, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Fluorescence, Mutation, Nervous System, Phenotype, Phosphorylation, Serine, Stem Cells, Time Factors, Blotting, Southern, Blotting, Western, Polymerase Chain Reaction, Phosphoglycerate Dehydrogenase, Mice
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