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Deciphering Cell-Autonomous Mechanisms for Fate Determination

Chang, AC;

Understanding the control of cell fate determination can provide insights for tissue development, immunity and disease evolution. With respect to tissue development, mitosis influences tissue architecture as the daughter cell requires its own space in the tissue microenvironment. The spatial dynamics during mitosis must be well controlled, otherwise the order of tissue homeostasis will break down. Therefore, in this thesis I focused in two chapters on dissecting the mechanism of daughter cell positioning. The results suggested Scribble and E-cadherin provide a platform to stabilise the morphological changes during mitosis, and potentially protect the daughter cells from being extruded. With respect to immunity, T cell development influences a major source of adaptive immunity. However, T cell development is not a straight-forward event of cell differentiation, but is propagated with multiple fate determination events such as survival, death, self-renewal or differentiation. One crucial test for fate determination in T cell development is the ?selection checkpoint. In this thesis, I found that HDAC6 inhibition during T cell development altered the control of ?-selection checkpoint, exposing a transitional population we called ‘DN3bPre’. My results suggested a profound fate determination must be coordinated in DN3bPre to ensure only the most qualified T cell is generated. Needless to mention, generating functional T cells can enhance the chance to combat cancer, but T cell generation per se is error-prone, which leads to leukaemia initiation. Therefore, a broad and deep understanding of fate determination during T cell development is urgent. Overall, in this thesis, I demonstrated molecular mechanisms that coordinate cell fate determination. Unlike many well-proven biological theory that fate determination is guided by extracellular signalling and cell-cell communication, the mechanisms I found are prone to be cellautonomous. That means fate determination of each cell in part is controlled by the cell itself. This is a mysterious driving force that involves the fingerprints of epigenetics such as HDAC6 activity takes the control of T cell fate. In this thesis I exposed multiple possibilities by which transcriptional control through HDAC6 might govern the cell-autonomous fate development. On the other hand, I found Scribble-E-cadherin complex plays a junctionalindependent role, which means the effect was not from neighbouring cells. This is a first time that the protein function of Scribble-E-cadherin is demonstrated as cell-autonomous signalling, and this attribute shapes cell division. Overall, my results contribute to deciphering cell fate determinations with cell-autonomous mechanisms.