UNIVERSITY OF MASSACHUSETTS

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. Interestingly, steroid levels rise at multiple stages during fly development, but they always die in response to a rise in hormone at a specific stage following cell growth arrest. 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 recent studies indicate that knock-down of either drosha or dicer, regulators of miRNAs, in salivary glands inhibit autophagy and degradation. Our hypothesis is that miRNAs regulate stage- and tissue-specific autophagic cell death by influencing either cell growth arrest, steroid signaling, autophagy or caspases. The regulation of autophagy could be direct, or could also occur by regulation of either steroid signaling or growth arrest. Studies of how miRNAs regulate salivary gland cell death should provide new mechanistic information about the regulation and role of autophagy in dying cells, and how cells die during development. Here we propose to: (1) determine how miRNAs regulate salivary gland cell death, and (2) identify the miRNAs that are expressed and function in salivary gland cell death. The association of autophagy with cancer indicates the importance of investigating miRNAs and their relationship to cell death.

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