Developmental Regulation of Growth, Size and Shape

DESCRIPTION (provided by applicant): It would be potentially advantageous if organs could be repopulated from a small number of cells that would remove and replace other cells during growth, preserving tissue dimensions during the replacement. Such a process can occur during development, where it is called "cell competition". Cell competition is seen during insect development, mammalian embryogenesis, and liver regeneration, and implicated in tumor development. When tissues contain genetically distinct cell populations with different growth properties, the `stronger'genotype can completely eliminate the `weaker'genotype and come to fill the entire compartment. We have identified 16 genes that are required for cell competition, and found that it depends on recognition, engulfment and killing of susceptible cells by their normal neighbors. Our current goal is a cellular and molecular understanding of the pathways that recognize and eliminate cells, how such cells become targets for removal, and undergo apoptosis when so targeted, and the mechanisms by which out-competed cells are replaced to preserve tissue morphology. As cell competition occurs during mammalian liver regeneration, and is implicated in cancer, it is anticipated that anti-tumor therapies and strategies to assist regeneration of human organs can be based on these studies. Defective cell survival and cell corpse engulfment underlie neurodegenerative diseases, neuronal injuries, heart attack, stroke, atherosclerosis, angiogenesis, and infectious diseases including HIV/AIDS, autoimmune diseases, and blindness. It is anticipated that, should it prove possible to manipulate cell engulfment and killing downstream of growth differences between cells, strategies may be developed for the replacement of developmental compartments that do not require manipulating oncogenes or tumor suppressors.