Incorporating calcium signalling in Vertex models of neural tube closure

Chakraborty, Abhishek 2024. Incorporating calcium signalling in Vertex models of neural tube closure. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Recent experiments have shown that apical constriction (AC) during neural tube closure (NTC) is driven by cell contractions preceded by asynchronous and cell-autonomous Ca2+ flashes. Disruption of these Ca2+ signals and contractions leads to neural tube defects, such as anencephaly. However, the inherent two-way mechanochemical coupling of Ca2+ signaling and mechanics is poorly understood, and live-cell imaging is difficult. Thus, models can help greatly but the few available partially reproduce experimental findings. We first study a modified implementation of the mechanochemical vertex model of Suzuki et al [196]; the modified Suzuki model. We numerically implement it by developing CelluLink, a new opensource (Python), user-friendly software package for vertex modelling. CelluLink’s parallel processing enables fast yet thorough parameter sweeps, guided by an analytically derived bifurcation diagram. CelluLink can be adapted to study other multicellular challenges. Subsequently, in close collaboration with experimentalists, we develop a one-way mechanochemical model to study the effect of Ca2+ on mechanics. This model significantly improves upon the Suzuki model, reproducing several experimental observations. We incorporate, for the first time, the surface ectoderm and the experimental Ca2+ flash amplitude and frequency profiles. Furthermore, guided by experiments, we model the damping coefficient of the vertices and cell-cell adhesion as functions of actomyosin concentration and cell size. The one-way model successfully reproduces the significant reduction in neural plate size during AC, within 2%-8% of the initial area. We then develop a two-way mechanochemical model which captures the two-way coupling between Ca2+ signals and mechanics. We incorporate stretch-sensitive Ca2+ channels, enabling the cell to respond to mechanical stimuli. The model reproduces the results of the one-way model, but more accurately, the Ca2+ frequency and amplitude arise from the interaction between the cells and are not imposed. We leverage our models to propose a series of hypotheses for future experiments.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Mathematics
Subjects:	Q Science > QA Mathematics
Funders:	Cardiff University - Vice Chancellor’s International Scholarship for Research Excellence
Date of First Compliant Deposit:	13 August 2024
Last Modified:	13 Aug 2024 15:31
URI:	https://orca.cardiff.ac.uk/id/eprint/171357

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