Marygold, Steven Jon; (2001) Characterization of genetic interactions between cell cycle regulators and armadillo in Drosophila melanogaster. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The Armadillo protein of Drosophila melanogaster is the pivotal transducer of the Wingless pathway, a signalling pathway that directs cell fate decisions during development. Cytoplasmic Armadillo is normally kept low by constitutive proteolysis. However, receipt of Wingless results in the stabilization of Armadillo and its transfer to the nucleus where it can activate gene transcription. Intriguingly, Armadillo is also necessary for cell-cell adhesion at epithelial adherens junctions. In order to explore how these two functions might be regulated and effected in vivo, a genetic modifier screen was conducted. One interacting mutation was a recessive lethal named l(3)neo401, but inconsistencies regarding the nature of the interaction and the cause of lethality put a stop to its further characterization. Armadillo 'loss-of-function' phenotypes in the adult wing are sensitive to the gene dosage of several regulators and targets of the mitotic kinase Cdk1, including Cyclin A, Cyclin B, String, Twins, and Cdk1 itself. Curiously, Dacapo and Cyclin E, negative and positive regulators of S phase entry respectively, exhibit similar interactions. The cell-biological reasons for these observations are unclear. Altering the genetic dosage of String also modifies wing phenotypes resulting from over-expression of Armadillo. The manner of these interactions indicates that String might be a negative regulator of Armadillo function. Indeed, increased String function reduces cytoplasmic Armadillo levels in imaginal disc cells, apparently through stimulating its proteolysis. String is an activating phosphatase of Cdk1 and is rate-limiting for mitotic entry in Drosophila cells. Consistent with this role and the results described above, mitotic cells have relatively low levels of cellular Armadillo and experimental induction of mitosis lowers cytoplasmic Armadillo. Thus, cell cycle-intrinsic down-regulation of Armadillo may function to reduce Wingless signalling and/or intercellular adhesion during cell division.

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