Building and breaking epithelial integrity in the neural tube: an optogenetic approach (360G-Wellcome-208758_Z_17_Z)

Using an innovative optogenetic approach within the zebrafish neural tube, I will directly explore how the polarity of individual cells drives the tissue organisation of a whole organ. In combination with 4D live imaging and functional abrogation, I will use light to specifically and reversibly manipulate apicobasal polarity, cleavage furrow formation and PI3K pathway signalling on a subcellular level. I will assess how apicobasal polarity and division are interrelated during morphogenesis of vertebrate epithelial tubes and how this relationship contributes to tissue integrity. Early zebrafish neuroepithelial divisions are highly predictable and coincident with de novo apicobasal polarisation. This provides a tractable model to assess a potential feedback loop between apical protein localisation and cleavage furrow positioning during epithelial establishment. The PI3K pathway is likely key to integrating apicobasal polarity with division. Within established epithelia, PI3K pathway defects are prevalent in cancers. I will manipulate PI3K pathway signalling within individual cells or groups of cells within an otherwise normal zebrafish neural tube. This in vivo method for manipulating cancer-linked signalling will allow me to test whether apicobasal polarity dysregulation is a cause or consequence of tissue disruption, providing clues to the cellular mechanisms of disease initiation.