A Novel Role for the 3′-5′ Exoribonuclease Dis3L2 in Controlling Cell Proliferation and Tissue Growth

In a complex organism, cell proliferation and apoptosis need to be precisely controlled in order for tissues to develop correctly. Excessive cell proliferation can lead to diseases such as cancer. We have shown that the exoribonuclease Dis3L2 is required for the correct regulation of proliferation in a natural tissue within the model organism <i>Drosophila melanogaster</i>. Dis3L2 is a member of a highly conserved family of exoribonucleases that degrade RNA in a 3′-5′ direction. We show that knockdown of <i>dis3L2</i> in the <i>Drosophila</i> wing imaginal discs results in substantial wing overgrowth due to increased cellular proliferation rather than an increase in cell size. Imaginal discs are specified in the embryo before proliferating and differentiating to form the adult structures of the fly. Using RNA-seq we identified a small set of mRNAs that are sensitive to Dis3L2 activity. Of the mRNAs which increase in levels and are therefore potential targets of Dis3L2, we identified two that change at the post-transcriptional level but not at the transcriptional level, namely <i>CG2678</i> (a transcription factor) and <i>pyrexia</i> (a TRP cation channel). We also demonstrate a compensatory effect between Dis3L2 and the 5′-3′ exoribonuclease Pacman demonstrating that these two exoribonucleases function to regulate opposing pathways within the developing tissue. This work provides the first description of the molecular and developmental consequences of Dis3L2 inactivation in a non-human animal model. The work is directly relevant to the understanding of human overgrowth syndromes such as Perlman syndrome.