Genetic characterisation of Emerin and Lamin A in zebrafish models of Emery-Dreifuss muscular dystrophy
2017-02-26T23:58:39Z (GMT) by
Emery-Dreifuss muscular dystrophy (EDMD) is a mild muscular dystrophy, which is characterised by specific muscle degeneration, joint contractures and cardiac conduction defects. Mutations in genes encoding LINC (LInker of Nucleoskeleton and Cytoskeleton) components contribute to about 40% of EDMD cases. The LINC complex is an evolutionarily conserved structure at the nuclear envelope (NE), which physically connects the nucleus to cytoplasm and regulates nucleokinesis. Exactly how defects in the NE generate the pathology evident in this disease remains unclear. There are two major hypotheses about the cause of EDMD: the first suggests that EDMD is caused by nuclear structural disruptions due to mechanical stress, while the other one proposes that some muscle specific aberrant signalling events lead to EDMD. This thesis examined the cellular basis of EDMD pathogenesis using zebrafish models. Our study established a number of zebrafish models of EDMD by inactivation of LINC components Emerin and Lamin A, and uncovered a series of EDMD-related pathologic events in mutant contexts at different developmental stages. I discovered that abnormal Notch signalling can be the primary pathogenic factor of the disease, which leads to aberrant somite segmentation and subsequent tissue specific defects in the Emerin and Lamin A deficient zebrafish. Taking advantage of the zebrafish model, I investigated the in vivo dynamics of Emerin and Lamin A at the NE. We showed that the molecular activities of Emerin and Lamin A are altered at the NE in the context of EDMD, which is in line with findings of mammalian cells in vitro. In addition, I discovered an unexpected novel “Emerin bridge” phenomenon, that EGFP-Emerin filaments from one nucleus dynamically interact with the adjacent nucleus within individual muscle fibres, implying the presence of intermolecular dynamics undefined at the NE. The results of this study can provide insights in the molecular basis of EDMD pathogenesis and be of direct therapeutic relevance.