Polarity development by asymmetric protein-cluster distributions in response to cortical flows in C. elegans zygotes
File(s)
Author(s)
McQuade, Jessica Aylish
Type
Thesis
Abstract
Asymmetric cell-division in the one-cell embryo is a key step in embryonic development. The initially homogeneous zygote establishes an anterior-posterior axis within the cell, allowing for the unequal distribution of cell fate determinants and subsequent cell differentiation. Therefore, polarity development is a fundamental procedure that defines the information template from which all future cell processes derive their cues. Many molecular players in polarity formation in C. elegans have been identified, but the design principles that underpin their interactions and how this contributes to successful polarisation remain unclear. This thesis focuses on the role of the clustering species PAR-3 and how its integration in the governing biochemical network promotes robust polarisation.
To correctly proceed to the two-cell stage, the foundational step of polarity formation must be responsive to the polarising cue and maintain established domains ready for downstream cell-cycle processes. We characterise global flows along the polarity axis and investigate coupling between the cortical flows and PAR-3 cluster sizes. We find there is no dynamic advantage for larger clusters and instead conclude all clusters flow with the same efficiency. Alternatively, we investigate whether enhancement of clusters is a response to mechanical forces within the cortex during the period of flow but find little direct evidence of this relationship. Rodriguez et al proposed kinase cycling between inactive (advective) and inactive (diffuse) state. We model two distinct reaction pathways through reaction-advection-diffusion simulation and assess their viability by implementation of Approximate Bayesian Computation. We find that direct binding through a flow-sensing, inactive state, followed by switching to a diffuse active state yields a network that is unviable and sensitive to perturbation. Sensitivity is alleviated when the advective species serves only to enhance independent binding of the active species. Therefore, we propose kinase cycling through this network motif as a mechanism towards enhanced robust polarisation.
To correctly proceed to the two-cell stage, the foundational step of polarity formation must be responsive to the polarising cue and maintain established domains ready for downstream cell-cycle processes. We characterise global flows along the polarity axis and investigate coupling between the cortical flows and PAR-3 cluster sizes. We find there is no dynamic advantage for larger clusters and instead conclude all clusters flow with the same efficiency. Alternatively, we investigate whether enhancement of clusters is a response to mechanical forces within the cortex during the period of flow but find little direct evidence of this relationship. Rodriguez et al proposed kinase cycling between inactive (advective) and inactive (diffuse) state. We model two distinct reaction pathways through reaction-advection-diffusion simulation and assess their viability by implementation of Approximate Bayesian Computation. We find that direct binding through a flow-sensing, inactive state, followed by switching to a diffuse active state yields a network that is unviable and sensitive to perturbation. Sensitivity is alleviated when the advective species serves only to enhance independent binding of the active species. Therefore, we propose kinase cycling through this network motif as a mechanism towards enhanced robust polarisation.
Version
Open Access
Date Issued
2021-09
Date Awarded
2022-03
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Endres, Robert
Publisher Department
Life Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)