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Hedgehog (Hh) morphogen signalling plays an essential role in tissue development and homeostasis. While much is known about the Hh signal transduction pathway, far less is known about the molecules that regulate the expression of the  hedgehog (hh)  ligand itself. Here we reveal that Shaggy (Sgg), the  Drosophila melanogaster  orthologue of GSK3β, and the N-end Rule Ubiquitin-protein ligase Hyperplastic Discs (Hyd) act together to co-ordinate Hedgehog signalling through regulating  hh  ligand expression and Cubitus interruptus (Ci) expression. Increased  hh  and Ci expression within  hyd  mutant clones was effectively suppressed by  sgg  RNAi, placing  sgg  downstream of  hyd . Functionally,  sgg  RNAi also rescued the adult  hyd  mutant head phenotype. Consistent with the genetic interactions, we found Hyd to physically interact with Sgg and Ci. Taken together we propose that Hyd and Sgg function to co-ordinate  hh  ligand and Ci expression, which in turn influences important developmental signalling pathways during imaginal disc development. These findings are important as tight temporal/spatial regulation of  hh  ligand expression underlies its important roles in animal development and tissue homeostasis. When deregulated,  hh  ligand family misexpression underlies numerous human diseases (e.g., colorectal, lung, pancreatic and haematological cancers) and developmental defects (e.g., cyclopia and polydactyly). In summary, our  Drosophila -based findings highlight an apical role for Hyd and Sgg in initiating Hedgehog signalling, which could also be evolutionarily conserved in mammals.

Regulation of hedgehog Ligand Expression by the N-End Rule Ubiquitin-Protein Ligase Hyperplastic Discs and the Drosophila GSK3β Homologue, Shaggy