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Tissue growth has to be carefully controlled to generate well-functioning organs. MicroRNAs are small non-coding RNAs that modulate the activity of target genes and play a pivotal role in animal development. Understanding the functions of microRNAs in development requires the identification of their target genes. Here, we find that , a conserved microRNA in the family, controls tissue growth and homeostasis in the wing imaginal disc. Upregulation of causes the repression of , the effector of the Hippo pathway in, and reduces tissue size. Remarkably, co-expression of and causes the formation of neoplastic tumors. We show that upregulation of represses the growth inhibitor, and depletion of cooperates with in the formation of neoplastic tumors. Hence, modulates a positive growth regulator,, and a negative growth regulator, Deregulation of this network can result in the loss of tissue homeostasis and the formation of tumors.

One of the fundamental issues in biology is understanding how organ size is controlled. Tissue growth has to be carefully regulated to generate well-functioning organs, and defects in growth control can result in tumor formation. The Hippo signaling pathway is a universal growth regulator and has been implicated in cancer. In Drosophila, the Hippo pathway acts through the miRNA bantam to regulate cell proliferation and apoptosis. Even though the bantam targets regulating apoptosis have been determined, the target genes controlling proliferation have not been identified thus far. In this study, we identify the gene tribbles as a direct bantam target gene. Tribbles limits cell proliferation by suppressing G2/M transition. We show that tribbles regulation by bantam is central in controlling tissue growth and tumorigenesis. We expand our study to other cell cycle regulators and show that deregulated G2/M transition can collaborate with oncogene activation driving tumor formation.

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