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Title: Examination of the Kirrel gene family during myogenesis
Author: Durcan, Peter Joseph
ISNI:       0000 0004 2724 9498
Awarding Body: Manchester Metropolitan University
Current Institution: Manchester Metropolitan University
Date of Award: 2012
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Somatic cell fusion is essential for the in vivo function of skeletal muscle, osteoclasts and trophoblasts. A diverse range of additional tissues including brain, heart, liver, prostate and intestinal epithelium are also subject to somatic cell fusion events in vivo. Fusion of embryonic stem cells has been reported and it has been hypothesised that fusion of cancer cells with macrophages may enable metastases. Furthermore, somatic cell fusion of Dystrophin positive cells with Dystrophin negative muscle cells may be therapeutically beneficial for the treatment of muscular dystrophy. In Drosophila, the type 1 transmembrane proteins Kin of Irre (Kirre), Roughest (Rst), Hibris and Sticks and Stones (SnS) are involved in regulating the muscle cell fusion process during larval development. The mammalian orthologues of Kirre and Rst include: Kirrel, Kirrel2 and Kirrel3 while Nephrin is the mammalian orthologue to Hibris and SnS. It is currently unclear whether the Kirrel family and Nephrin are expressed in mammalian skeletal muscle cells and whether they regulate the cell fusion process in these cells, as is the case in Drosophila. It was therefore hypothesised that all Kirrel family members and Nephrin would be temporally expressed in mammalian skeletal muscle cells as they undergo cell fusion events and hence may regulate the somatic cell fusion process. It was further hypothesised that inhibition of fusion would alter their expression patterns. Presented within this thesis are novel findings regarding the detection and expression profiling of all Kirrel family members and Nephrin during in vitro myogenesis of the C2C12 murine skeletal muscle cell line. Previously unreported splice variants of Kirrel and Kirrel3 have also been identified in C2C12 cells and in additional murine tissues. Variable expression patterns among family members are reported. The presence of multiple Kirrel family members and Nephrin in C2C12 cells suggest that redundancy and/or compensatory mechanisms are in place, as is the case in Drosophila, with regards mammalian muscle cell fusion in vivo. Results presented within this thesis lay the foundations for improving understanding of the molecular mechanisms underpinning mammalian somatic cell fusion events during development, injury repair and hypertrophy and also may enable increased efficacy of cellular therapies for diseases such as muscular dystrophy and the prevention of cancer metastasis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available