The interaction between Tankyrase and Axin modulates Wingless signaling during development. Ofelia Tacchelly Benites, Zhenghan Wang, Eungi Yang, Michael Randall, Yashi Ahmed. Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH.

   The Wnt/Wingless pathway directs cell fate decisions, cell proliferation, and apoptosis during development in metazoans. Deregulation of the Wnt/Wingless pathway is involved in a number of developmental diseases and cancers. Targeted proteasomal degradation of the transcriptional activator beta-catenin controls the levels of Wnt/Wingless pathway activity, and this degradation depends on the activity of the destruction complex. Axin is a rate-limiting component of the destruction complex and an increase in Axin levels inhibits Wnt/Wingless signaling in many contexts. Recently, the poly-ADP-ribose polymerase Tankyrase has been shown to promote Axin turnover in cultured carcinoma cells. This interaction is thus an attractive therapeutic target for diseases in which beta-catenin regulation is lost. However, understanding the importance of Tankyrase in regulating Axin and Wnt/Wingless signaling in vivo has not been successful in vertebrates, because of functional redundancy in vertebrate Tankyrase genes. There is only one fly Tankyrase gene and it is highly conserved, thus making Drosophila an ideal system to study the significance of Tankyrase mediated Axin regulation. Using a Drosophila model, we have shown that loss of Tankyrase and deletion of the Tankyrase binding domain of Axin lead to an aberrant stabilization of Axin and loss of Wingless signaling. Here, we provide the first in vivo evidence that Tankyrase and the Tankyrase binding domain of Axin are required to promote multiple developmental processes that are dependent on Wnt/Wingless signaling.