During the progression from zygote to adult organism, signals from multiple pathways are integrated in progressively restricted ways to produce differentiated cell types. Programmed cell death, or apoptosis, is an integral part of this process, yet the mechanisms restricting this fate to specific cells at specific times are poorly understood. In humans, mutations affecting regulation of the cell death program cause disease including cancers. Delineating these mechanisms will identify reagents for improved diagnosis of disease and targets for improved therapies. Analysis of the core pathway of programmed cell death in Caenorhabditis elegans serves as an essential foundation for understanding the more complex pathways of apoptosis in mammals. Here I extend the work on the core components of the cell death pathway in C. elegans to study how programmed cell death is regulated in specific cells during normal development. I have developed a powerful gfp-based reporter assay to detect and analyze cell death in a specific set of neurons, and used this method to identify candidate genes regulating programmed death in these cells. Among these genes are three whose m a m malian homologues have intriguing but poorly understood links to oncogenesis and blood and nervous system development. My work in C. elegans suggests previously unsuspected links between developmental pathways and I begin here to test whether these links are conserved for the mammalian homologues. In this way I will use the extraordinarily powerful methods available in C. elegans for analysis of how mutations affect cell fates to test models of how mutant mammalian genes are oncogenic.
|Prasad, Brinda; Karakuzu, Ozgur; Reed, Randall R et al. (2008) unc-3-dependent repression of specific motor neuron fates in Caenorhabditis elegans. Dev Biol 323:207-15|
|Liu, Huarui; Strauss, Tamara J; Potts, Malia B et al. (2006) Direct regulation of egl-1 and of programmed cell death by the Hox protein MAB-5 and by CEH-20, a C. elegans homolog of Pbx1. Development 133:641-50|
|McLaughlin, Margaret E; Robson, Caroline D; Kieran, Mark W et al. (2003) Marked regression of metastatic pilocytic astrocytoma during treatment with imatinib mesylate (STI-571, Gleevec): a case report and laboratory investigation. J Pediatr Hematol Oncol 25:644-8|