The work proposed here is intended to elucidate the mechanisms by which cells that fail to adopt appropriate fate induce programmed cell death. Normal development and homeostasis requires proper specification and cellular differentiation. However, interference with the establishment of cellular fates and cellular functions can lead to the induction of cell death. This strategy might guard the organism against developmental errors, because if these cells were not removed, they might cause malignancies such as cancer. However, under pathological conditions the same strategy may cause the inappropriate death of cells giving rise to congenital defects during development or other conditions such as neurodegenerative disorders. Thus, a detailed investigation of the underlying mechanisms will provide new insights into human diseases in which deregulation of apoptosis is known to occur and may lead to new strategies for therapeutic intervention. It is unknown why a cell dies that receives no or an incorrect developmental signal. In the genetic model organism Drosophila melanogaster, a number of mutants exist that block normal cellular specification and differentiation. Subsequently, these cells undergo cell death. Thus, these mutants provide an excellent genetic model to study the regulation and onset of this form of cell death. We have determined that cellular mis- specification is the underlying cause of cell death in these mutants. The cell death-inducing gene hid is specifically up-regulated in mis-specified cells, suggesting that mis-specification-induced cell death is the result of an active gene-directed process. We postulate that a mechanism monitors the cell's ability to develop correctly. If the cell fails to do so, the monitoring mechanism triggers the transcriptional induction of hid and induces cell death. To genetically and molecularly characterize the postulated monitoring mechanism we will (1) analyze the promoter of the hid gene and identify the factor(s) binding to it in response to mis-specification, (2) analyze the genetic requirement of a number of genes identified in a microarray analysis for mis- specification-induced cell death, and (3) perform genetic screens to identify genes which are required for this process. It is the goal of this proposal to gain a comprehensive understanding of the mechanisms underlying this interesting biological phenomenon, and to exploit this knowledge for therapeutic purposes. ? ? This project investigates the mechanisms by which cells die if they do not receive the correct developmental information. These incorrectly informed cells resemble cancer cells, and the observation that they die may protect the organism from several common diseases. Understanding the mechanisms of this process may lead to new therapeutic interventions for cancer, and may also be relevant for treatment of neurodegenerative diseases. ? ? ?
