Identification and Characterization of Genes Required For Compensatory Growth in Drosophila

To maintain tissue homeostasis, some organs are able to replace dying cells with additional proliferation of surviving cells. Such proliferation can be localized (e.g. a regeneration blastema) or diffuse (compensatory growth). The relationship between such growth and the growth that occurs during development has not been characterized in detail. Drosophila melanogaster larval imaginal discs can recover from extensive damage, producing normally sized adult organs. Here we describe a genetic mosaic system to screen for recessive mutations that impair imaginal disc recovery following tissue damage. By generating clones of cells carrying a temperature-sensitive cell-lethal mutation, we conditionally ablate patches of tissue in the imaginal disc. We can then assess the ability of the surviving sister clones to replace the ablated tissue. This occurs by non-localized compensatory proliferation and an increase in the overall rate of tissue growth together with a small prolongation of the proliferative phase of disc development. We have used this system to identify several mutations that selectively compromise compensatory growth and have developed a modified whole-genome re-sequencing (WGS) strategy to identify the relevant genes. We demonstrate that these mutations interfere with imaginal disc recovery following ablation in distinct ways. We find that many of the mutations identified disrupt genes with roles in developmental growth. A decrease in the function of such genes may be particularly deleterious under conditions of more rapid growth, as occurs during compensatory growth and some types of tissue overgrowth. Finally. the approach we describe is applicable to the study of compensatory growth in diverse tissues in Drosophila.