CONICET | Buscador de Institutos y Recursos Humanos

Fine-tuned Notch and Hedgehog signaling pathways via attenuators and dampers have long been recognized as importantmechanisms to ensure the proper size and differentiation of many organs and tissues. This notion is further supported byidentification of mutations in these pathways in human cancer cells. However, although it is common that the Notch andHedgehog pathways influence growth and patterning within the same organ through the establishment of organizingregions, the cross-talk between these two pathways and how the distinct organizing activities are integrated during growthis poorly understood. Here, in an unbiased genetic screen in the Drosophila melanogaster eye, we found that tumour-likegrowth was provoked by cooperation between the microRNA miR-7 and the Notch pathway. Surprisingly, the molecularbasis of this cooperation between miR-7 and Notch converged on the silencing of Hedgehog signalling. In mechanisticterms, miR-7 silenced the interference hedgehog (ihog) Hedgehog receptor, while Notch repressed expression of the brotherof ihog (boi) Hedgehog receptor. Tumourigenesis was induced co-operatively following Notch activation and reducedHedgehog signalling, either via overexpression of the microRNA or through specific down-regulation of ihog, hedgehog,smoothened, or cubitus interruptus or via overexpression of the cubitus interruptus repressor form. Conversely, increasingHedgehog signalling prevented eye overgrowth induced by the microRNA and Notch pathway. Further, we show thatblocking Hh signal transduction in clones of cells mutant for smoothened also enhance the organizing activity and growthby Delta-Notch signalling in the wing primordium. Together, these findings uncover a hitherto unsuspected tumoursuppressor role for the Hedgehog signalling and reveal an unanticipated cooperative antagonism between two pathwaysextensively used in growth control and cancer.