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Type of publication: Diploma Thesis
Type of document:

Year: 2011

Authors: Klammer, Silvana

Title: Untersuchung der gewebsspezifischen Segregation von mitochondrialer DNA in heteroplasmatischen Mäusen.

Other title: Examination of tissue-specific segregation of mitochondrial DNA in heteroplasmatic mice.

Source: Diplomarbeit, Vet. Med. Univ. Wien, pp. 50.


Advisor(s):

Steinborn Ralf

Reviewer(s):
Brem Gottfried

Vetmed Research Units:
VetCore


Graduation date: 27.10.11


Abstract:
Eventually, a mammalian in vivo model system is necessary in order to answer the multiple questions, that still remain, in terms of mtDNA biology, mitochondrial disease pathogenesis and tissue specificity. Though the number of published mammals studies in literature about tissue-specific segregation of various mtDNA genotypes (mitotypes) and their possible causes and development mechanisms is relatively small and confined to mouse, human and prospectively to non human apes. The limitation for mice is the low variability of the mtDNA of the existing laboratory mouse strains. While science has enabled the synthesis of a complete circular mitochondrial genome, it is not yet possible to transmit it to a living cell. The aim of this research was to analyze the mtDNA segregation pattern in various tissues of a newly created mouse model. The heteroplasmatic mouse model was generated by means of ooplasmatic transfer from two mitotypes of the West European house mouse (Mus musculus domesticus). One of the two genotypes was a laboratory mouse strain (C57Bl/6N, mitotype 1), the other a wild mouse strain from Southern Germany (Hohenberg, mitotype 3). An age-related, tissue-specific segregation of the donor mtDNA (mitotype 3) could be demonstrated in four out of eight examined tissues by using the Amplification Refractory Mutation System-qPCR. A new type of tissue-specific mtDNA distribution pattern was found in liver, spleen and blood. For the first time, also a tissue-specific effect in the heart could be documented. The amount of donor mtDNA is declining at the beginning, but stabilizes after some time. Furthermore it could be proven that the tissue-specific segregation already started during embryonic development. These results can be explained with the combination of mitotype 1 and 3. The tissue-specific segregation pattern would be explicable by selection of mitotype 3 over mitotype 1 in interaction with the applied nuclear background of C57Bl/6N. The causes of the tissue-specific segregation of various mitotypes, which are unresolved up to now, could be researched by further molecular genetic studies. A better understanding of the nuclear mitochondrial interaction or of the allelic variants would be a major step towards understanding diseases, which are based on mtDNA mutations.


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