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Biomechanical and genetic analysis of neural tube closure in the mouse embryo

Marshall, Abigail Rose; (2021) Biomechanical and genetic analysis of neural tube closure in the mouse embryo. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Development of the neural tube (NT), the embryonic precursor to the brain and spinal cord, consists of bending and folding of the neural plate into a complete tube during neural tube closure (NTC). Cells and tissues undergo gross changes in position and shape throughout NTC, for which the underlying mechanism ultimately depends on integration of their biomechanics. This thesis focuses on the biomechanical role of the surface ectoderm (SE), the layer of cells that overlies the closing neural folds, in spinal NTC. Techniques which allow investigation of the biomechanical properties of cells and tissues include cell shape analysis, laser ablation and expression analysis of genes involved in force generation and detection. Throughout this thesis, these techniques are used to probe SE biomechanics in wild type mouse embryos, and in Grhl-2 and -3 mutant embryos. Grhl-2 and -3 are SE-expressed transcription factors, and mutations in these genes lead to severe neural tube defects (NTDs), making them a valuable model for studying the role of the SE in NTC. Characterisation of the wild type SE revealed an elongation of SE cells along the rostrocaudal midline. Surprisingly, functional analysis reveals this is not due to high rostrocaudal tension, challenging the classical view that cell shape can be used to predict the forces that cells are under, and raising the hypothesis that elongation may be a result of intrinsic cell behaviour. The characteristic elongated SE cell shape is lost in Grhl2 mutants, which also show significantly abnormal cell and tissue level recoil after laser ablation, and disrupted YAP and actomyosin expression. One of the most significant differentially expressed genes in Grhl2 mutants is E-cadherin. Experimental disruption of E-cadherin function supports the importance of this molecule in causing biomechanical abnormalities – together, these results suggest that cell-cell adhesion is an important player in driving normal closure of the NT. Further studies in this thesis show that NTDs in Grhl3 gain- and loss-of function mutants are not due to the same molecular mechanisms as for Grhl2. RNA sequencing suggests a novel role of desmosomes, which are also important in cell-cell adhesion. Finally, a novel mechanism which may contribute to severe NTDs in Vangl2Lp;Grhl3ct double mutants is explored. Although this thesis does not support reduced tailbud proliferation as a causative mechanism, a novel genetic interaction between Vangl2Lp and overexpression of Grhl3 is identified.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Biomechanical and genetic analysis of neural tube closure in the mouse embryo
Event: UCL
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Biology and Cancer Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10127479
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