Nikolaidou, Kyriaki; (2002) Investigation of the role of Rho GTPase signalling in cell shape changes during Drosophila morphogenesis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Morphogenesis, the generation of the shape of an organism, requires several cellular processes including cell migration, cell division and cell shape changes. These processes are mainly mediated by the cell cytoskeleton, which is regulated in part by Rho family of small GTPases. One activator of Rho that is known to be important in morphogenetic cell shape change is RhoGEF2. RhoGEF2 is itself activated by Folded gastrulation and Concertina during gastrulation. Genetic interactions between folded gastrulation or concertina and RhoGEF2 were apparent in developmental processes other than gastrulation, showing conservation of a signalling pathway that activates cell shape change. Protein Kinase N and Serum Response Factor, both known targets of Rho signalling, interact, presumably indirectly, with RhoGEF2. Alleles of ten putative novel Rho signalling pathway components also interact with RhoGEF2, indicating the existence of other proteins involved in regulation of cell shape change in morphogenesis. Signalling through Rho results in many diverse outcomes. One major question in the field relates to the mechanism used by this single protein to select a particular outcome. The hypothesis tested here is that the individual guanine nucleotide exchange factor that activates Rho participates in the selection. If this is the case, activation of the exchange factor would be expected always to result in the same outcome. From a series of experiments it is shown that RhoGEF2 promotes shape changes and epithelial folding in all tissues studied, but has no observed effect on any other Rho-mediated processes studied. The cellular and molecular function of RhoGEF2 was analysed during gastrulation. Time-lapse monitoring of the dynamic process of gastrulation in wild type embryos revealed features that have not been observed in fixed tissues. RhoGEF2 appears to be important in the accumulation of myosin, presumably for apical cellular constriction. RhoGEF2 possibly receives several signals during gastrulation, one of which is likely to be from the FGF receptor Heartless. If this is the case, it explains many unanswered questions regarding the regulation of cell shape change in Drosophila gastrulation.

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