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 involves specific regulatory mechanisms that integrate with core autophagy pathways that are conserved from yeast to humans. We have made the surprising discovery that engulfment genes are induced before autophagic cell death, and that the engulfment receptor drpr is required for tissue autonomous autophagy and degradation of salivary glands. Our goal is to characterize the engulfment 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 engulfment genes in the regulation of autophagy and death of salivary glands, (2) investigate the regulation and function of engulfment receptors during autophagy, and (3) investigate the signaling downstream of Drpr and determine how Drpr regulates autophagy. The recent association of autophagy with neurodegenerative disorders and cancer indicates the importance of investigating the understudied process of autophagic programmed cell death.

Public Health Relevance

Programmed cell death plays an important role during animal development, and defects in this process are associated with a variety of human disorders including cancer and autoimmunity. We are studying the relationship between autophagy and programmed cell death during development. The recent association of autophagy with neurodegenerative disorders and cancer illustrates the importance of investigating the relationship between autophagy and cell death.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM079431-09
Application #
8608540
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Maas, Stefan
Project Start
2007-02-01
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
9
Fiscal Year
2014
Total Cost
$318,308
Indirect Cost
$124,808
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
MariƱo, Guillermo; Niso-Santano, Mireia; Baehrecke, Eric H et al. (2014) Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 15:81-94
Nelson, Charles; Baehrecke, Eric H (2014) Eaten to death. FEBS J 281:5411-7
Nelson, Charles; Ambros, Victor; Baehrecke, Eric H (2014) miR-14 regulates autophagy during developmental cell death by targeting ip3-kinase 2. Mol Cell 56:376-88
Nelson, Charles; Baehrecke, Eric H (2014) Autophagy and cell death in the fly. Methods Enzymol 545:181-99
Tracy, Kirsten; Baehrecke, Eric H (2013) The role of autophagy in Drosophila metamorphosis. Curr Top Dev Biol 103:101-25
Chang, Tsun-Kai; Shravage, Bhupendra V; Hayes, Sebastian D et al. (2013) Uba1 functions in Atg7- and Atg3-independent autophagy. Nat Cell Biol 15:1067-78
McPhee, C K; Balgley, B M; Nelson, C et al. (2013) Identification of factors that function in Drosophila salivary gland cell death during development using proteomics. Cell Death Differ 20:218-25
Mou, Xiaochun; Duncan, Dianne M; Baehrecke, Eric H et al. (2012) Control of target gene specificity during metamorphosis by the steroid response gene E93. Proc Natl Acad Sci U S A 109:2949-54
Rong, Yueguang; McPhee, Christina K; McPhee, Christina et al. (2011) Spinster is required for autophagic lysosome reformation and mTOR reactivation following starvation. Proc Natl Acad Sci U S A 108:7826-31
Nezis, Ioannis P; Shravage, Bhupendra V; Sagona, Antonia P et al. (2010) Autophagic degradation of dBruce controls DNA fragmentation in nurse cells during late Drosophila melanogaster oogenesis. J Cell Biol 190:523-31

Showing the most recent 10 out of 23 publications