During development multicellular organisms remove unwanted cells by apoptosis, or programmed cell death. These cells are recognized and internalized by other living cells via phagocytosis, a mechanism highly conserved from nematodes to humans. Apoptosis plays an important role in the establishment and maintenance of tissue architecture, and serves as a quality-control mechanism by eliminating cells that are infected, abnormal, or tumorigenic. Phagocytosis of apoptotic cells not only ensures that these functions are correctly executed; more importantly, by removing dying cells before they release harmful cellular contents, it actively prevents tissue injury, inflammation, and auto-immune responses. My long-term objective is to understand the mechanisms that control the phagocytic clearance of apoptotic cells. One particular aspect I study is what makes an apoptotic cell distinguishable from a normal living cell by phagocytic cells. In mammals it has been observed that phosphatidylserine (PS) is exposed on the outer surface of the cell membrane during apoptosis and acts as an """"""""eat me"""""""" signal. Recent studies have identified a secreted protein that specifically binds PS, milk fat globule-EGF-factor 8 (MFG-E8). Using MFG-E8::GFP as a reporter I observed that PS is specifically expressed on the surface of apoptotic cells in C. elegans. I propose to identify signaling pathways that lead to the exposure of PS on the surface of apoptotic cells and the role of PS in subsequent engulfment of those cells using C. elegans as a model organism.
Specific Aim 1 : To determine the effects of phosphatidylserine presentation on engulfment of apoptotic cells in C. elegans.
Specific Aim 2 : To determine the role of C. elegans scramblase homologs and in PS presentation and cell corpse engulfment.
Specific Aim 3 : To identify novel genes involved in cell corpse engulfment and the presentation of a phosphatidylserine """"""""eat me"""""""" signal through genetic analyses. ? ? ?
| Wu, Hsiao-Huei; Bellmunt, Elena; Scheib, Jami L et al. (2009) Glial precursors clear sensory neuron corpses during development via Jedi-1, an engulfment receptor. Nat Neurosci 12:1534-41 |
