Steroid Regulation of Drosophila Programmed Cell Death

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

Programmed cell death plays an important role during animal development, and defects in this process result in a variety of human disorders including cancer and autoimmunity. Apoptosis and autophagic cell death are the two most prominent morphological forms of programmed cell death that occur during development. The regulation of apoptosis is relatively well understood, but little is known about the mechanisms that mediate autophagic programmed cell death. We are studying autophagic programmed cell death during development of the fruit fly Drosophila melanogaster using larval salivary gland cell death as a model. An increase in steroid triggers a genetic hierarchy that activates nearly synchronous cell death in salivary glands. These developmentally-regulated cell deaths utilize apoptosis genes, including caspase proteases, but inhibition of caspases and caspase mutations only partly inhibit salivary gland degradation. Salivary glands possess the morphology of cells that die by autophagic cell death, and autophagy is required for their complete degradation. While much is known about the function and regulation of autophagy in yeast, less is known about the mechanisms that regulate this fundamental process in animal cells, and little is known about the function of autophagy in programmed cell death. Our hypothesis is that the cell-specific use of autophagy in multicellular organisms requires mechanisms that differ from yeast. Our goal is to characterize critical factors that regulate autophagy, and investigate how their regulation is coordinated in the context of autophagy that participates in cell death during development. Here we propose to: (1) determine the function of Atg4-related genes during salivary gland cell death, (2) determine the function of engulfment genes in dying salivary glands, and (3) determine the relationship between steroid-triggered degradation of salivary glands and genes that regulate autophagy. The recent association of autophagy with neurodegenerative disorders and cancer indicates the importance of investigating the understudied process of autophagic programmed cell death.