H. Robert Horvitz

Speaker: H. Robert Horvitz

Title: The Genetic Control of Apoptosis and Cellular Reprogramming in the Nematode Caenorhabditis Elegans


Apoptosis (programmed cell death) is a normal feature of animal development and tissue homeostasis. The misregulation of cell death has been implicated in such human disorders as cancer, autoimmune diseases, heart attacks, stroke and neurodegenerative diseases. Our laboratory has analyzed the mechanisms responsible for programmed cell death by studying the nematode Caenorhabditis elegans. We have characterized developmentally, genetically and molecularly the roles of genes that function in C. elegans programmed cell deaths. Many of the C. elegans genes involved in programmed cell death are structurally and functionally similar to genes that act in mammalian apoptosis, indicating that the major mechanisms of programmed cell death are evolutionarily conserved. A few cell deaths occur in the absence of the activity of any of the components of the well-characterized caspase-mediated killing pathway. These deaths display features of apoptosis, occur in mutants defective in all four C. elegans caspase genes (caspases generally drive apoptosis in worms and other organisms) and involve cells that normally are killed rapidly by the core killing pathway but that in the absence of this pathway still die but do so more slowly. We propose that for some cells that undergo programmed cell death two distinct mechanisms of cell killing act to ensure that cells that should die do so. We also are examining the problem of cellular reprogramming using C. elegans. Specifically, we are analyzing the mechanistic basis of a case of in vivo reprogramming in which neurons are generated from mesodermal cell lineages. We hope that these studies will lead to the identification of genes and pathways that, like those of apoptosis, are conserved from nematodes to humans.