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Mitochondrial transcription factor A is necessary for mtDNA maintance and embryogenesis in mice

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.

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References

  1. Larsson, N.G. & Clayton, D.A. Molecular genetic aspects of human mitochondrial disorders. Anna Rev. Genet. 29, 151–178 (1995).

    Article  CAS  Google Scholar 

  2. Schon, E.A., Hirano, M. & DiMauro, S. Mitochondrial encephalomyopathies: Clinical and molecular analysis. J. Bioenerg. Biomembr. 26, 291–299 (1995).

    Article  Google Scholar 

  3. Wallace, D.C. Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256, 628–632 (1992).

    Article  CAS  Google Scholar 

  4. Clayton, D.A. Replication and transcription of vertebrate mitochondrial DNA. Annu Rev. Cell Biol. 7, 453–478 (1991).

    Article  CAS  Google Scholar 

  5. Parisi, M.A. & Clayton, D.A. Similarity of human mitochondrial transcription factor 1 to high mobility group proteins. Science 252, 965–969 (1991).

    Article  CAS  Google Scholar 

  6. Dairaghi, D.J., Shadel, G.S. & Clayton, D.A. Addition of a 29 residue carboxyl-terminal tail converts a simple HMG box-containing protein into a transcriptional activator. J. Mol. Biol. 249, 11–28 (1995).

    Article  CAS  Google Scholar 

  7. Larsson, N.G., Garman, J.D., Oldfors, A., Barsh, G.S. & Clayton, D.A. A single mouse gene encodes the mitochondrial transcription factor A and a testis-specific nuclear HMG-box protein. Nature Genet. 13, 296–302 (1996).

    Article  CAS  Google Scholar 

  8. Larsson, N.G., Barsh, G.S. & Clayton, D.A. Structure and chromosomal localization of the mouse mitochondrial transcription factor A gene (Tfam). Mamm. Genome 8, 139–140 (1997).

    Article  CAS  Google Scholar 

  9. Gu, H., Marth, J.D., Orban, P.C., Mossmann, H. & Rajewsky, K. Deletion of a DNA polymerase β gene segment in T cells using cell type-specific gene targeting. Science 265,103–106 (1994).

    Article  CAS  Google Scholar 

  10. Lewandoski, M., Meyers, E.N. & Martin, G.R. Fgf8 gene function in vertebrate development. Cold Spring Harbor Symp. Quant. Biol. (in press).

  11. Lakso, M. et al. Targeted oncogene activation by site-specific recombination in transgenic mice. Proc. Natl. Acad. Sci. USA 89, 6232–6236 (1992).

    Article  CAS  Google Scholar 

  12. Stuart, E.T., Kioussi, C. & Gruss, P., Pax genes. Annu. Rev. Genet. 28, 219–236 (1994).

    Article  CAS  Google Scholar 

  13. Pikó, L. & Chase, D.G. Role of the mitochondrial genome during early development in mice. J. Cell Biol. 58, 357–378 (1973).

    Article  Google Scholar 

  14. Pikó, L. & Matsumoto, L. Number of mitochondria and some properties of mitochondrial DNA in the mouse egg. Dev. Biol. 49, 1–10 (1976).

    Article  Google Scholar 

  15. Pikó, L. & Taylor, K.D. Amounts of mitochondrial DNA and abundance of some mitochondrial gene transcripts in early mouse embryos. Dev. Biol. 123, 364–374 (1987).

    Article  Google Scholar 

  16. Ebert, K.M., Liem, H. & Hecht, N.B. Mitochondrial DNA in the mouse preimplantation embryo. J. Reprod. Fertil.. 82, 145–149 (1988).

    Article  CAS  Google Scholar 

  17. Lewandoski, M., Wassarman, K.M. & Martin, G.R., Zp3-cre, a transgenic mouse line for the activation or inactivation of loxP-flanked target genes specifically in the female germ line. Curr. Biol. 7, 148–151 (1997).

    Article  CAS  Google Scholar 

  18. Attardi, G. et al, in Mitochondrial Genes (eds Slonimski, P., Borst, P. & Attardi, G.) 51–71 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1982).

    Google Scholar 

  19. Lansman, R.A. & Clayton, D.A. Selective nicking of mammalian mitochondrial DNA in vivo: photosensitization by incorporation of 5-bromodeoxyuridine. J. Mol. Biol. 99, 761–776 (1975).

    Article  CAS  Google Scholar 

  20. England, J.M., Costantino, P. & Attardi, G. Mitochondrial RNA and protein synthesis in enucleated African green monkey cells. J. Mol. Biol. 119, 455–462 (1978).

    Article  CAS  Google Scholar 

  21. Ostronoff, L.K., Izquierdo, J.M. & Cuezva, J.M. mt-mRNA stability regulates the expression of the mitochondrial genome during liver development. Biochem. Biophys. Res. Common. 217, 1094–1098 (1995).

    Article  CAS  Google Scholar 

  22. Polosa, P.L. & Attardi, G. Distinctive pattern and translational control of mitochondrial protein synthesis in rat brain synaptic endings. J. Biol. Chem. 15, 10011–10017 (1991).

    Google Scholar 

  23. Tybulewicz, V.L.J., Crawford, C.E., Jackson, P.K., Bronson, R.T. & Mulligan, R.C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell 65, 1153–1163 (1991).

    Article  CAS  Google Scholar 

  24. Hogan, B., Beddington, R., Constantini, F. & Lacy, E. . in A Laboratory Manual. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1994).

    Google Scholar 

  25. Wood, S.A., Alien, N.D., Rossant, J., Auerbach, A. & Nagy, A. Non-injection methods for the production of embryonic stem cell-embryo chimaeras. Nature 365, 87–89 (1993).

    Article  CAS  Google Scholar 

  26. Larsson, N.G., Oldfors, A., Garman, J.D., Barsh, G.S. & Clayton, D.A. Down-regulation of mitochondrial transcription factor A during spermatogenesis in humans. Hum. Mol. Genet. 6, 185–191 (1997).

    Article  CAS  Google Scholar 

  27. Rustin, P. et al. Biochemical and molecular investigations in respiratory chain deficiencies. Clin. Chim. Acta. 228, 35–51 (1994).

    Article  CAS  Google Scholar 

  28. Michael, N.L. . et al. All eight unassigned reading frames of mouse mitochondrial DNA are expressed. EMBO J. 3, 3165–3175 (1984).

    Article  CAS  Google Scholar 

  29. Taanman, J.W., Burton, M.D., Marusich, M.F., Kennaway, N.G. & Capaldi, R.A. Subunit specific monoclonal antibodies show different steady-state levels of various cytochrome-c oxidase subunits in chronic progressive external ophthalmoplegia. Biochim. Biophys. Acta. 1315, 199–207 (1996).

    Article  Google Scholar 

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Larsson, NG., Wang, J., Wilhelmsson, H. et al. Mitochondrial transcription factor A is necessary for mtDNA maintance and embryogenesis in mice. Nat Genet 18, 231–236 (1998). https://doi.org/10.1038/ng0398-231

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