Abstract
The regulation of mitochondrial DNA (mtDNA) expression is crucial for mitochondrial biogenesis during development and differentiation. We have disrupted the mouse gene for mitochondrial transcription factor A (Tfam; formerly known as m-mtTFA) by gene targetting of loxP-sites followed by cre-mediated excision in vivo. Heterozygous knockout mice exhibit reduced mtDNA copy number and respiratory chain deficiency in heart. Homozygous knockout embryos exhibit a severe mtDNA depletion with abolished oxidative phosphorylation. Mutant embryos proceed through implantation and gastrulation, but die prior to embryonic day (E)10.5. Thus, Tfam is the first mammalian protein demonstrated to regulate mtDNA copy number in vivo and is essential for mitochondrial biogenesis and embryonic development.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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DNA, Mitochondrial*
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / metabolism
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Embryo Implantation
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Female
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Fetal Death / genetics*
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Fetal Growth Retardation / genetics
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Gene Dosage
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Gene Expression Regulation, Developmental*
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Heart / embryology
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Heterozygote
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High Mobility Group Proteins
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Integrases / genetics
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Mice
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Mice, Knockout
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Mitochondria / metabolism
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Mitochondria / pathology
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Mitochondrial Proteins*
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Mutation
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Nuclear Proteins*
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Phosphorylation
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Transcription Factors / genetics*
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Transcription Factors / metabolism
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Viral Proteins*
Substances
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DNA, Mitochondrial
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DNA-Binding Proteins
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High Mobility Group Proteins
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Mitochondrial Proteins
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Nuclear Proteins
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Tfam protein, mouse
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Transcription Factors
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Viral Proteins
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mitochondrial transcription factor A
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Cre recombinase
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Integrases