Regulation of Hippo signaling by Atrophin in the developing Drosophila wing.

Organ development is directed through integration of signaling networks and their transcriptional programs. Investigation of connections between Hippo signaling and the transcriptional co-repressor Atrophin reveals that Atrophin modulates Hippo signaling outputs in the developing Drosophila wing in distinct ways in different regions. Near the dorsal-ventral boundary, loss of Atrophin leads to upregulation of targets of the Hippo pathway transcription factor Yorkie. This is explained by impairment of Notch signaling and consequent downregulation of Vestigial, which normally competes with Yorkie for binding to Scalloped. In proximal regions of the wing disc, loss of Atrophin leads to downregulation of Yorkie activity. This is explained by downregulation of Dachs, as Dachs inhibits Warts, the central kinase controlling Yorkie activity. Downregulation of Dachs is explained by modulation of its upstream regulators Dachsous and Four-jointed, which is explained in turn by our discovery that Atrophin interacts genetically and physically with Vestigial and competes with Scalloped for Vestigial binding. These studies define new roles for Atrophin and enhance our understanding of the interplay of transcriptional activators and repressors that modulate Hippo signaling to shape wing development.