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Title: The role of mitotic rounding in spindle assembly and positioning
Author: Dimitracopoulos, A.
ISNI:       0000 0004 8503 4794
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Cells entering mitosis undergo adhesion disassembly, osmotic changes and membrane remodelling, which contribute to mitotic rounding. At the same time actin filaments are cross linked to the membrane increasing cell mechanical rigidity, and microtubules become shorter and highly dynamic compared to interphase, allowing for the search and capture of chromosomes and the formation of the mitotic spindle. Then, by following intracellular and extracellular cues, motor proteins anchored at the membrane control the spindle position and orientation, which in turn allow for precise control over symmetry and orientation of cell division. In this thesis, I have explored the role of mitotic cell rounding in spindle assembly and positioning. By interfering with adhesion disassembly, it is possible to keep cells flat in mitosis. This leads to a delay in mitotic spindle morphogenesis. This was caused by defects in chromosome capture that result from the limited reach of astral-microtubules, which fail to rescale to span the full width of flat mitotic cells. The limit in microtubule reach also affects division symmetry by preventing the mitotic spindle from interacting with the cell extremities in order to become positioned at the cell centre. Taking this approach further, by preventing centrosome separation and only allowing monopolar spindles to form in flat mitotic cells, it was possible to reveal an intrinsic instability that drives spindle positioning. Monopolar spindles are subject to forces that pull on the centrosome through the interaction of astral-microtubules with cortically localised motor proteins. Using this system we were able to uncover a feedback control system linking DNA, astral-microtubules, motor proteins, and the actin cortex, and to isolate and study the interactions between the individ-ual components. By extending these findings to unperturbed cells, we believe we have gained a better understanding of the mechanisms underlying efficient bipolar spindle assembly, and the control of bipolar spindle positioning in rounding mitotic cells.
Supervisor: Baum, B. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available