Glutathione synthesis is essential for mouse development but not for cell growth in culture

Zheng-Zheng Shi, Joseph Osei-Frimpong, Geeta Kala, Subbarao V. Kala, Roberto Barrios, Geetha M. Habib, Dana J. Lukin, Christopher M. Danney, Martin M. Matzuk, Michael W. Lieberman

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Glutathione (GSH) is a major source of reducing equivalents in mammalian cells. To examine the role of GSH synthesis in development and cell growth, we generated mice deficient in GSH by a targeted disruption of the heavy subunit of γ-glutamylcysteine synthetase (γGCS-HS(tm1)), an essential enzyme in GSH synthesis. Embryos homozygous for γGCS-HS(tm1) fail to gastrulate, do not form mesoderm, develop distal apoptosis, and die before day 8.5. Lethality results from apoptotic cell death rather than reduced cell proliferation. We also isolated cell lines from homozygous mutant blastocysts in medium containing GSH. These cells also grow indefinitely in GSH-free medium supplemented with N-acetylcysteine and have undetectable levels of GSH; further, they show no changes in mitochondrial morphology as judged by electron microscopy. These data demonstrate that GSH is required for mammalian development but dispensable in cell culture and that the functions of GSH, not GSH itself, are essential for cell growth.

Original languageEnglish (US)
Pages (from-to)5101-5106
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number10
StatePublished - May 9 2000

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