Roles of Hippo and Ecdysone Receptor Signaling in the regulation of dronc

The Hippo pathway is an evolutionarily conserved pathway that regulates organ size and tissue homeostasis in Drosophila and mammals. The pathway functions by regulating the nuclear availability of transcriptional cofactor Yorkie (Yki), mammalian YAP, which is regulated by the activity of a core kinase cascade comprising the serine threonine kinases Hippo (Hpo) and Warts (Wts) and their accessory proteins. Yki binds with transcription factors like Scalloped (Sd) or Homothorax (Hth) to regulate target genes involved in cell proliferation and survival. Downregulation of the Hpo pathway causes increased cell proliferation and overgrowth, whereas hyperactivation of this pathway leads to cell death due to activation of caspases. Caspase proteins are cysteine aspartic proteases which play essential roles in cellular signaling and development via apoptosis. We showed that the initiator caspase dronc (mammalian Caspase 9) is a transcriptional target of Yki. We found that loss of Hippo signaling leads to downregulation of dronc expression, whereas downregulation of Sd resulted in upregulation of dronc expression. We also found that known binding partner of Sd like E2F1 is also involved in regulating dronc expression. Earlier studies have shown that dronc expression is regulated by the Ecdysone receptor (EcR) signaling pathway and mapped a EcR regulatory element on dronc promoter. We found that depletion of EcR or its corepressors like Smrter caused upregulation of dronc expression. Overexpression of Taiman (Tai) a binding partner of EcR and Yki also upregulated dronc expression. We also show that Tai-Yki interaction may not be required for dronc regulation. We hypothesize that dronc expression is regulated by the Hippo and EcR signaling pathways. Here, we present our work on the regulation of dronc by the Hippo and EcR signaling pathways, and its implications on development.