Dampening the signals transduced through hedgehog via microRNA miR-7 facilitates Notch-induced tumourigenesis

Abstract

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