Dis3L2 regulates cell proliferation and tissue growth through a conserved mechanism

Dis3L2 is a highly conserved 3’-5’ exoribonuclease which is mutated in the human overgrowth disorders Perlman syndrome and Wilms’ tumour of the kidney. Using Drosophila melanogaster as a model system, we have generated a new dis3L2 null mutant together with wild-type and nuclease-dead genetic lines in Drosophila to demonstrate that the catalytic activity of Dis3L2 is required to control cell proliferation. To understand the cellular pathways regulated by Dis3L2 to control proliferation, we used RNA-seq on dis3L2 mutant wing discs to show that the imaginal disc growth factor Idgf2 is responsible for driving the wing overgrowth. IDGFs are conserved proteins homologous to human chitinase-like proteins such as CHI3L1/YKL-40 which are implicated in tissue regeneration as well as cancers including colon cancer and non-small cell lung cancer. We also demonstrate that loss of DIS3L2 in human kidney HEK-293T cells results in cell proliferation, illustrating the conservation of this important cell proliferation pathway. Using these human cells, we show that loss of DIS3L2 results in an increase in the PI3-Kinase/AKT signalling pathway, which we subsequently show to contribute towards the proliferation phenotype in Drosophila. Our work therefore provides the first mechanistic explanation for DIS3L2-induced overgrowth in humans and flies and identifies an ancient proliferation pathway controlled by Dis3L2 to regulate cell proliferation and tissue growth.
Author summary Regulation of cell proliferation is not only important during development but also required for repair of damaged tissues and during wound healing. Using human kidney cells as well as the fruit fly Drosophila we have recently discovered that cell proliferation can be regulated by a protein named Dis3L2. Depletion or removal of this protein results in excess proliferation. These results are relevant to human disease as DIS3L2 has been shown to be mutated in an overgrowth syndrome (Perlman syndrome) where affected children have abnormal enlargement of organs (e.g. kidneys) and susceptibility to Wilms’ tumour (a kidney cancer). Dis3L2 is an enzyme known to "chew up" mRNA molecules which instruct the cell to make particular proteins. Using state-of-the-art molecular methods in Drosophila, we have discovered that Dis3L2 targets a small subset of mRNAs, including an mRNA encoding a growth factor named 'imaginal disc growth factor 2' (idgf2). For human kidney cells in culture, we have found that depletion of DIS3L2 results in enhanced proliferation, and that this involves a well-known cellular pathway. Our results mean that we have discovered a new way of controlling cell proliferation, which could, in the future, be used in human therapies.