3 Materials and Methods
5.5 Conclusions and Perspectives
In summary, during the work leading up to this thesis, a novel mouse model with expression of the hPARP-1 by ectopic gene targeting in murine ES cells was generated, using an „ends-out‟
gene replacement vector. Unexpectedly, bidirectional elongation of the vector homology arms to more than 40 kb and subsequent integration of the targeting vector at an adjacent position on chromosome 1 mimicked site-specific homologous recombination and gene replacement. As predicted by the DSB repair model, these data demonstrate that in ES cells the synthesis-dependent strand annealing pathway can also operate during classical gene targeting. As ectopic gene targeting has so far only been described for „ends-in‟ integration-type vectors in non-ES cell gene targeting (McCulloch et al. 2003), the ectopic gene targeting event of the present thesis is of general importance: It shows a critical caveat for future gene targeting approaches, especially when generating knock-in mice. Typically, in this context the loss of protein expression of the endogenous targeted gene cannot easily be assessed during screening. Here, two reliable techniques, i.e. qPCR and FISH analysis, were validated to detect ectopic gene targeting in vitro before injecting ES cell into blastocysts to generate homozygous knock-in mice.
In the hPARP-1 model generated during this work, „hetero-dimerization‟ of the endogenous m1 and the ectopic h1 might influence 1 activity and consequently PARP-1-dependent cellular functions. Such an interference can be excluded in hypermorphic hPARP-1 or “super-PARP-1” knock-in mice with functional exchange of mPARP-1. [N.B. super-PARP-1 carries a gain-of-function mutation at amino acid position 713 (L713F; section 1.1.2.3) (Miranda et al. 1995)]. Therefore, in future approaches, functional replacement of mPARP-1 with hypermorphic PARP-1 variants might be accomplished by alternative strategies. One feasible approach could include a recombination-mediated cassette exchange strategy via gene targeting combined with the Cre/loxP system, which enables exchanges of genomic sequences of >100 kb. This approach has recently been demonstrated suitable for the generation of an alpha globin-humanized mouse model, however requiring at least two successive rounds of gene targeting (Wallace et al. 2007). Alternatively, a knock-in strategy could be employed using a smaller targeting vector than the one used in this thesis: Exon 1 of the mParp-1 locus could be targeted by introducing cDNA sequences of hypermorphic enzymes, thereby disrupting mParp-1 gene transcription and putting the cDNA sequences under the transcriptional control of cis and trans-acting murine regulatory elements. The latter strategy could be accomplished with a targeting vector of less than 20 kb and should give rise to a functional knock-in in a single round of ES cell gene targeting. It will be interesting to compare the phenotype of the hPARP-1 mice generated in the present study to such hypermorphic knock-in mice and also to conventional PARP-1-over-expressing transgenic mice.
Expression analyses demonstrated a gene-dose-dependent expression of full-length hPARP-1 with a content of about 50% of total PARP-1 in homozygous hPARP-1 mice. Total PARP-1 expression was moderately increased in these mice. In vitro experiments suggested that poly(ADP-ribosyl)ation is altered in hPARP-1-expressing cells, while clonogenic survival of hPARP-1 ES cells is unaltered, thus indicating that the ectopic enzyme is functional. Analyses of hPARP-1 mice revealed several unexpected phenotypes: higher mortality, alterations of energy metabolism, impaired regenerative potential, kyphosis, splenomegaly, and glomerulopathy. This outcome points to a multifaceted pathological phenotype. Due to the genetic background variability of the mice used in the present study and the manifold cellular functions of PARP-1, these pathologies could evolved by several, possibly overlapping molecular mechanisms. To elucidate these mechanisms, in a next step, a detailed study regard to clinical chemistry and hematology is indicated. Furthermore, it will be interesting to see which phenotype will become manifest on a C57BL/6 genetic inbred background of coisogenic mutant mice (F10).
Although it cannot be fully excluded that transcription of additional loci might be affected by ectopic gene targeting, the observed phenotypes are potentially related to ectopic hPARP-1 expression as outlined in the previous section. This indicates that PARP-1-dependent poly(ADP-ribosyl)ation in the mouse is a well-balanced and fine-tuned physiological mechanism and alterations in either direction, i.e. both ablation, as was shown by studies of Parp-1 knock-out mice, and enhancement, as suggested by this thesis, cause detrimental effects on an organismal level.
The present work has characterized the occurrence of ectopic gene targeting in murine ES cells transfected with an „ends-out‟ gene replacement vector for the first time and has moreover established hPARP-1 mice as a novel model system in poly(ADP-ribosyl)ation research. The evaluation of the underlying molecular mechanisms of the unexpected, multifaceted phenotypes should contribute to further elucidating the role of PARP-1 both in health and disease. This could also form a new basis for pharmacological intervention in human disease.
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