Browsing by Author "Jacobs, Craig Timothy"

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    Notch signalling in spinal cord patterning: Crosstalk and fate decisions
    (2021-07-19) Jacobs, Craig Timothy; Huang, Peng; Hansen, David; Brook, William
    The spinal cord is a highly complex structure. During development, initially equivalent neural progenitors divide and give rise to a specific pattern of differentiated neurons. Understanding how this pattern arises would have far reaching impact, not just in developmental biology but also in the understanding of developmental disorders. Building on the decades of work from other groups, this thesis focuses on the extrinsic cues that guide pattern formation in the zebrafish spinal cord, with particular focus on the highly conserved Notch signalling pathway. The major, and most well studied, role of Notch signalling during neural development is progenitor maintenance. This thesis explores the additional roles of Notch signalling in signalling crosstalk and cell fate decisions. The action of Hedgehog signalling during spinal cord development is well characterised, providing the spatial information to drive the patterning of the ventral neural progenitors. In chapter two, I reveal a novel mechanism by which Notch signalling maintains Hedgehog response in spinal cord progenitors. This occurs at the level of the Gli family of downstream transcription factors, not at the primary cilia as previous reports suggest. This raises the interesting question of whether the Notch mediated control of Hh signalling is providing the instructive cues that guide fate determination in the ventral spinal cord. In chapter three, I analyse this through examining the Notch signalling dynamics of the lateral floor plate domain. This reveals that different cell types in the lateral floor plate display discrete durations of Notch signalling. It is the duration of Notch signalling that instructs cell fate determination, as prolonged exposure is required for the later-born cell fates. How the neighbouring progenitors in the lateral floor plate temporally restrict their Notch response remains an open question, though it is likely mediated through differential ligand-receptor interactions. Collectively, this thesis highlights the pleiotropic nature of Notch signalling during neural development. Alongside the classical involvement in progenitor maintenance, Notch signalling also functions to maintain cellular response to key developmental signals and directly guide cell fate decisions.