Papastergios, Evangelos Vasileios; (2022) Cellular and molecular mechanisms of neural tube formation and axial elongation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

During primary neurulation, the flat neural plate folds into a hollow tube which later forms the brain and spinal cord. Primary neurulation begins with elongation and bending of the neural plate, bringing its lateral folds into contact. It is then completed through a process of “zippering”, whereby the neural folds progressively fuse along the antero-posterior axis of the embryo. Previous research from our lab highlighted the importance of the extracellular matrix receptor integrin β1 for successful neural fold fusion and suggested an interaction with fibronectin. The current project investigated the role of fibronectin in neural tube formation. As fibronectin production and trafficking dynamics were unclear, three conditional knock-out strategies were employed to target fibronectin in a variety of tissues. Assessment of mutant embryos in terms of morphology, fibronectin localisation and associated cellular processes revealed two distinct roles of fibronectin in spinal development. First, fibronectin produced by the surface ectoderm at the posterior neuropore fusion site was found to be important in the formation of cellular semi-rosettes that facilitate zippering. Second, fibronectin produced primarily by the paraxial mesoderm was shown to be necessary for mechanical coupling and symmetric elongation of neural and mesodermal tissues. Elongation of the caudal trunk and tail of the embryo is underpinned by the continuous incorporation of neuromesodermal progenitors (NMPs) in the tailbud region. While NMPs are often defined based on the co-expression of the neural marker Sox2 and the mesodermal marker T/Brachyury, lineage tracing experiments from our lab indicated that Sox2-expressing cell derivatives colonise only the neural tube after E8.5. This project consolidated these findings by employing RNAscope to validate the previously used SoxCreERT2 line and to evaluate Sox2 expression in NMPharbouring regions. Furthermore, Sox2 was deleted in NMPs, and mutant embryos were examined in terms of developmental progression, and NMP colonisation, fate choice and genetic compensation.

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