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Title: The role of biomechanics and signalling in zebrafish joint morphogenesis
Author: Brunt, Lucy
ISNI:       0000 0004 5921 8063
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2015
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During the development of the skeletal system, immature joints must undergo joint morphogenesis to produce joint structures that are specialised for their function. In conditions such as Developmental dysplasia of the hip, abnormal joint morphogenesis can cause joint dislocations and if left untreated, can lead to osteoarthritis. Although it is well established that biomechanical strain from muscle activity is required for accurate shaping ofthe joint, the role of signalling events downstream of mechanical cues remains less well understood. Also, the exact contribution of dynamic changes to cell behaviour at the joint, such as cell differentiation, migration, cell orientation, cell death and proliferation is still unclear. In this thesis, using zebrafish as a model system, I show that cellular events such as cell proliferation, migration and cell orientation work in concert to change the morphology of the zebrafish jaw joint in the early larval stages when the joints are first used. I demonstrate that these cellular processes are affected in the absence of muscle activity, causing abnormal joint morphogenesis. I have developed the first Finite Element models for the zebrafish skeletal system and through these I show that high levels of compressive strain are located at jaw regions prone to aberrant morphology changes. I show that Wnt signalling is active in regions of high strain at the jaw and that loss of muscle activity leads to loss of local Wnt signalling. I then demonstrate the involvement of Wnt signalling in joint morphogenesis by using pharmacological and genetic manipulations of the canonical and non-canonical Planar Cell Polarity Wnt pathways. Manipulation of both leads to altered joint shape, despite the continued presence of muscle activity, placing Wnt downstream of muscle force. Finally I identify a mutant for the TGF-beta family, gdfS, and demonstrate that it responds mechanosensitively at the jaw joint.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available