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• W757148045 abstract "In contrast to homozygous mutations heterozygous germline mutations of the Sonic Hedgehog (Shh) receptor Patched (Ptch) are not lethal and predispose with a high incidence to the formation of basal cell carcinomas (BCC), medulloblastomas (MB) and rhabdomyosarcomas (RMS). Since somatic biallelic inactivation of Ptch is essential for the development of BCC, Ptch is thought to be a tumor suppressor gene. However, recently it has been shown that monoallelic loss of Ptch is sufficient for formation of RMS and MB. The goal of this PhD work was to analyse the pathogenesis of Ptch-associated RMS in more detail. In addition the attempt was made to identify the cell of orgin of these tumors. At first we were able to show that the formation of RMS in heterozygous Ptchneo67/+ mice can be explained by an imbalance of the expression levels of the mutant and the wildtype (wt) Ptch allele. In this context the expression of the mutant allele is increased, whereas the expression of the wt allele is decreased in RMS. To verify this observation, different splice variants of Ptch from RMS tissue were analysed. Next, it was shown that the Shh/Ptch signalling pathway can be activated both by expression of the mutant Ptch protein and by reduction of wt Ptch. Based on these results a model for the development of Ptch-associated RMS was proposed, in which tumor formation is induced by an inactivating mutation of one Ptch allele and the additional silencing of the remaining allele (Uhmann A et al., 2005). A more detailed analysis of the development of Ptch-associated tumors included the characterization of a mutant mouse line that allows for deletion of Ptch in a conditional, biallelic manner in adult mice. Using an inducible Cre-recombinase Ptch was ubiquitously inactivated in adult mice. Within a short time this led to hyperproliferative changes of the skin, of the gastro-intestinal tract and of the mesenterium. Furthermore, deletion of Ptch induced a severe defect of T and B cell development in thymus and bone marrow. This defect resulted in a depletion of immature peripheral B cells and in a complete loss of T cells in the thymus (Uhmann A et al., 2006). In addition, the local induction of the Cre-recombinase activity in the muscle induced the development of BCC after 90 days, but not of RMS or other defects. Beyond, transgenic mouse lines were established and characterized that express an inducible Cre-recombinase under the control of the murine Pax7 promotor. Using the conditional Ptch knock-out model, these mouse lines should help to delete Ptch specifically in satellite cells (adult stem cells of the skeletal muscle). This aproach should supply evidence that RMS develop from satellite cells. Until now it was not possible to activate the Cre-recombinase in satellite cells. However, an activation of the Cre-recombinase was detected in neural structures of the skeletal muscle, in which the Pax7 promotor is also active. Hence the established transgenic mice could possibly serve as a new model for analysing development und regenerative processes of peripheral nerves." @default.
• W757148045 created "2016-06-24" @default.
• W757148045 creator A5049181564 @default.
• W757148045 date "2022-02-20" @default.
• W757148045 modified "2023-09-23" @default.
• W757148045 title "Der Hedgehog Rezeptor Patched bei der Tumorentstehung und in der Hämatopoese" @default.
• W757148045 doi "https://doi.org/10.53846/goediss-3601" @default.
• W757148045 hasPublicationYear "2022" @default.
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