Marshall, F.J.; (2006) Wingless degradation in Drosophila imaginal discs. Doctoral thesis , University of London.

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Abstract

Wingless is a secreted signalling molecule with multiple roles in patterning developing Drosophila. Previous work has shown that in the Drosophila embryonic epidermis, regulated degradation controls the distribution of Wingless protein, leading to an asymmetric range. The actual mechanism of Wingless degradation is not currently understood. I have used gain and loss of function experiments to examine the role of the signalling receptors, Dffizzled-2 and Arrow, in the control of Wingless degradation. Receptor mediated degradation can be subdivided into three steps: capture, endocytosis and targeting to lysosomes. Dfrizzled-2 is understood to play a key role in capture and indeed when Dfrizzled-2 is overexpressed, Wingless is stabilised at the cell surface. I have shown that Wingless and Dfrizzled-2 also colocalise in endocytic structures and by using mutants of Dfrizzled-2,1 have shown that Dfrizzled-2 is actively involved in the endocytosis of Wingless. Dfrizzled-2 therefore appears to function in the first two steps towards degradation, capture and endocytosis, however it is clearly not sufficient for degradation as when overexpressed, Dfrizzled-2 stabilises Wingless. This suggests that a limiting factor is absent that prevents Wingless captured by DFrizzled-2 from being degraded. I investigated the possibility that this limiting factor could be Arrow. I have shown that indeed, Arrow brings about the degradation of the Dfrizzled-2-Wingless complex. This activity is specific to Dfrizzled-2, since Arrow does not cause degradation of Wingless stabilised by Dally-like, another Wingless receptor. My results have led to a model where there is a division of labour between the two signalling receptors Dfrizzled-2 has functions in capture and endocytosis and Arrow, while also contributing somewhat to endocytosis, brings the signal that directs Wingless to lysosomes. Further investigations have been carried out to identify the specific motifs in Arrow that target Wingless to degradation.

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