Understanding the cellular pathways regulated by Dis3L2 in cell proliferation.

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Regulation of cell proliferation is of crucial importance to all multicellular organisms. Cells must proliferate throughout development in order for the organism to grow from an egg to an adult. Proliferation must also occur to repair damaged areas during the process of wound healing. Control of proliferation is vitally important to allow individual animals and their constituent organs to grow to reach and not exceed their correct sizes, as well as to maintain symmetry between the left and right sides of an animal. Uncontrolled cell proliferation is a hallmark of cancer with many genes involved in growth and proliferation implicated in cancer progression. Using fruit flies as a model organism, we have recently discovered that cell proliferation can be regulated by an enzyme named Dis3L2. This enzyme is known to destroy messenger RNA molecules (mRNAs) which instruct the cell to make particular proteins. By comparing mutant fruit flies lacking Dis3L2 with normal individuals, we have found that lack of Dis3L2 results in wings that are much larger than normal. The wings grow from larval wing imaginal discs, which are also much larger in the mutant. Our results are particularly interesting because mutations in the equivalent human gene, DIS3L2, result in Perlman syndrome and susceptibility to a kidney cancer called Wilms' tumour. Perlman syndrome is an overgrowth condition where affected children display pre-natal gigantism and abnormal enlargement of organs (e.g. kidneys). Therefore mutations in Dis3L2 in both fruit flies and humans result in the overgrowth of cells within some organs, showing an excellent conservation of this biological pathway between these organisms and demonstrating the usefulness of fruit flies to understand this disease.Using state-of-the-art molecular methods, we have discovered that a lack of Dis3L2 results in an increase in levels of a few specific mRNAs. The known function of some of these mRNAs suggest a molecular pathway for understanding the function of Dis3L2 in flies and humans. Our hypothesis is that Dis3L2 normally controls proliferation by limiting energy production within the cell as well as regulating the levels of important cellular resources. Since proliferating cells require more energy to fuel their rapid growth, this hypothesis is consistent with the tissue overgrowth we see in our fruit flies. We have the expertise, as well as the molecular and genetic tools to test this hypothesis. The proposed project is entirely novel; as yet no research group has elucidated the mechanisms whereby Dis3L2 controls proliferation in the natural context of a developing organism. Previous studies have used individual tissue culture cells or immortalised cells in culture rather than normal cells in a natural tissue therefore have missed clues about the cellular pathways involved. Since the cellular pathways controlling growth in fruit flies are very similar to those in humans, the knowledge gained during this project may help us to to understand the ways that normal tissues grow and develop. This knowledge will also be useful in finding ways to promote controlled regeneration of tissues such as that which occurs during liver regeneration. It will also be important in the search for therapies to combat uncontrolled proliferation, as occurs during cancer. Should our experiments confirm that Dis3L2 controls proliferation via metabolic pathways, this will provide a powerful way of combatting cancer as it will be difficult for cancer cells to circumvent their need for high metabolic rates. This project will therefore provide valuable insights into a new cellular pathway which can be used in the development of new disease therapeutics.