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Title: Investigating the interplay between cellular mechanics and decision-making in the C. elegans germ line
Author: Atwell, Kathryn
ISNI:       0000 0004 6494 7738
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2016
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The behaviour of individual cells must be carefully coordinated across a tissue to achieve correct function. In particular, proliferation and differentiation decisions must be precisely regulated throughout development, tissue maintenance, and repair. A better understanding of how these processes are controlled would have implications for human health; cancer is, after all, dysregulated proliferation, while regenerative medicine relies on being able to influence cell decisions accurately. To investigate such fundamental biological processes, it is common practice to use an experimentally tractable model organism. Here, we focus on the germ line of the nematode worm C. elegans, which provides opportunities to study organogenesis, tissue maintenance, and ageing effects. Despite the advantages of this organism as a biological model, certain questions about germ cell behaviour and coordination remain challenging to address in the lab. There is therefore a need for computational models of the germ line to complement experimental approaches. In this thesis, we develop a new in silico model of the C. elegans germ line. Novel aspects include working in three dimensions, covering the late larval period, and integrating a logical model of germ cell behaviour into a wider cell mechanics simulation. Our model produces a reasonable fit to wild-type germline behaviour, and provides the first cell tracking and labelling predictions for the larval period. It also suggests two new biological hypotheses: 1) that “stretching” growth plays a significant role in gonadogenesis, and 2) that a feedback mechanism acts on the germ cell cycle to prevent overproliferation. Having introduced the full model, we address some technical questions arising from our work, namely: what is the effect of applying a more physically realistic force law?; and can simulation performance be improved by changing the numerical scheme? Finally, we use in silico modelling to compare a number of hypothesised germ line maintenance mechanisms. There, our results support a model with functionally equivalent germ cells undergoing at most infrequent, transient cell cycle arrests.
Supervisor: Dunn, Sara-Jane ; Osborne, James ; Gavaghan, David ; Kugler, Hillel ; Baker, Ruth Sponsor: Engineering and Physical Sciences Research Council ; Microsoft Research Cambridge
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Computational biology ; C. elegans ; cell based modelling ; stem cell ; simulation ; numerical methods