Cell competition in development and homeostasis

The genes that control many aspects of cellular function are contained on chromosomes in the cell nucleus. If these genes or the chromosomes that carry them become damaged, many aspects of cell function can be altered. Gene and chromosome changes can cause birth defects, accumulate during aging, are found in nearly every cancer, and are thought to have many adverse effects on health. This proposal hypothesizes that a set of 80 genes, dispersed around the various chromosomes, are exploited to recognize cells with large-scale genetic changes and eliminate them before they affect health. These genes encode ribosomal proteins, each one of which assembles into a unique position in the ribosome, so that ribosome assembly is affected if any are limiting. Studies in the fruitfly Drosophila document a regulatory pathway that is activated by ribosomal protein gene imbalance and that leads to cell elimination by cell competition with nearby normal cells. One goal of this proposal is to verify that ribosomal protein genes, and the regulatory genes that respond to their imbalance, are able to target cells with genetic damage for competitive elimination, and to define the range of genome damage that is subject to this regulatory mechanism in somatic tissues. A second goal is to assess the role of cell competition in protecting the germline from aneuploid genetic changes that might lead to birth defects. These studies make use of targeted genetic recombination methods using fruitfly chromosomes. These studies will establish the importance and scope of a newly-recognized mechanism that can remove cells with large-scale genetic damage, and which may play an important role in the prevention of birth defects and of cancer, as well as in healthy aging and prevention of age-related diseases.