Research Interests

Apoptosis is a major form of cell death in animals that helps the survival of organisms.  Inability to eliminate mutated and potentially dangerous cells is associated with cancers, while many neurodegenerative disorders are due to excess apoptosis.  In developing tissues of complex animals, there is a tight coordination between the rate of apoptosis and cell proliferation that helps tissues to reach a predetermined size.  Even massive elimination of damaged cells during development is beneficial, as the cell loss can be efficiently replaced by compensatory proliferation. On the other hand, cells acquire resistance to apoptosis once they exit the cell cycle and enter a differentiation program, which prevents the loss of vital cells that cannot be replaced.  Our major interest in the laboratory is to understand how the cellular death machinery acts to coordinate apoptosis and proliferation during Drosophila development.

At the molecular level, caspases and their regulators constitute the core apoptotic machinery.  Similar to the apoptosis mechanisms in mammals, effector caspase activation triggers apoptosis in Drosophila.  Effector caspases, in turn, are activated by Apoptosomes, a holoenzyme complex which contains, at its core, the initiator caspase, Dronc together with Apaf1.  Our results indicate that loss of Diap1’s ability to ubiquitylate Dronc for degradation promotes Apoptosome assembly and triggers cell death.  Moreover, when effector caspases are blocked in these cells, active Apoptosomes reveal their growth-promoting role by activating JNK signaling and inducing secreted growth factors such as wingless and dpp (Ryoo et al., 2004).  This has led us to propose that apoptotic cells may have a mitogenic activity that instructs neighboring cells to undergo compensatory proliferation, thereby assuring tissue size homeostasis in proliferating organs.

Our second research program is aimed at understanding how endoplasmic stress (ER-stress) activates apoptosis.  ER-stress is frequently caused by unfolded proteins in the ER, and is thought to be a cause of a wide variety of disorders, including alzheimer’s disease, parkinson’s disease, retinitis pigmentosa, multiple myeloma and diabetes.  Although apoptosis is a pathologically relevant outcome of ER-stress, how caspases become activated under these conditions remains poorly characterized.  We have begun investigating the Drosophila genes that make up the cellular response machinery to ER-stress, also known as the Unfolded Protein Response (UPR).  Through this effort, we found that the Drosophila xbp1 mRNA undergoes unconventional splicing in response to ER-stress, through the activity of an ER-tethered endonuclease, ire1.  This property was used to generate an ER-stress sensor where GFP is expressed in frame only after xbp1 mRNA splicing.  Significantly, xbp1 splicing and ER-chaperone induction occurs in the Drosophila model for the Autosomal Dominant Retinitis Pigmentosa (ADRP), where the expression of mutant rhodopsin-1 molecules leads to late onset retinal degeneration. These developments provide a basis to investigate how ER-stress activates apoptosis in Drosophila disease models (Ryoo et. al., submitted).  Ongoing efforts aim to examine existing hypotheses and to identify new components linking ER-stress and caspase activation.