有效率的清除由計畫性細胞死亡（PCD, Program Cell Death）所產生的死細胞是免疫系統機制中極為重要的一環，此舉將可避免發炎反應以及因死細胞釋放自體抗原所引發自體免疫反應，進而降低對個體的傷害。
本篇報告針對一個在各個物種間皆具高度保守度的基因PSR (Phosphatidylserine receptor)進行功能上的探討，結果發現此一原本發現於哺乳動物巨嗜細胞上可專一辨識死細胞所釋出的PS（Phosphatidylserine）訊息的受器─ 而此一基因的相似物ps-1在線蟲的細胞吞噬作用中也扮演了類似的角色， psr-1 可在吞噬細胞作用，由於在過量表現CED-2, CED-5, CED-10, 及CED-12的情況下psr的缺失性狀可被回復，且在非活體環境下可偵測到PSR可與CED-5以及CED-12結合，因而推論PSR-1的功能應為一作用於CED-2/CrK II, CED-5/Dock180, CED-10/Rac-1,與CED-12/ELMO-1此一保守訊息傳遞路徑上游的受器。
除此之外，經實驗證實另一已被證實在哺乳動物的死細胞吞噬機制中亦扮演角色的磷酸脢受器(a receptor tyrosine kinase)─mer不但也參與在線蟲死細胞吞噬過程，而且經遺傳實驗顯示其同樣位在CED-2, CED-5, CED-10與CED-12等分子上游；再經由更進一步的雙重突變實驗認為，mer 可能與psr共同作用，接收外界的訊息以活化CED-2/CrK II, CED-5/Dock180, CED-10/Rac-1,與CED-12/ELMO-1此一保守訊息傳遞路徑，進而驅動細胞骨架重組造成吞噬動作。

Apoptosis, or programmed cell death, is considered as the most physiological mode of cell death, which is used to dispose the unwanted cells. In vivo, apoptotic cells are efficiently removed by professional or nonprofessional phagocytes, which is a process thought to be essential for tissue remodeling and the resolution of inflammation. In mammalian system, macrophage recognizes apoptotic cells by several mechanisms, including recognition of the exposed phosphatidylserine (PS).
We suggest that psr, a highly conserved phosphotidylserine receptor, not only play a role in mammalian macrophage but also function in the cell corpse engulfment in C. elegans. Cell —specific expression of psr-1(C. elegans psr homologue) indicates that psr-1 functions in engulfing cell to control cell corpse engulfment. Heat shock bypass experiments suggest that psr-1 likely acts upstream of the conserved GTPase signaling pathway mediated by CED-2/CrkII, CED-5/Dock180, CED-10/Rac1 and CED-12/ELMO-1 to control the phagocytosis of cell corpses. Furthermore, we also showed that PSR could interact physically with CED-5 and CED-12 in vitro.
In addition, we found that mer, a member of Axl/Mer/tryo3 receptor tyrosine kinase, is also important in the process of cell corpse engulfment based on the phenotype analysis of cmer (RNAi) mutants. Our genetic data showed that cmer (C. elegnas mer homologue) likely also acts upstream of ced-2, ced-5, ced-10 and ced-12. The experiments in combination with our double mutant analysis suggest that PSR-1 and cMER might act together to initiate the signaling mediated by CED-2/CrkII, CED-5/Dock180 and CED-12/ELMO-1 and results in activation CED-10/Rac-1, which in turn cause cell corpse engulfment through reorganization of cytoskeleten.

中文摘要 1
Abstract 2
Introduction
Overview of apoptosis 3
Engulfment of apoptotic cells 3
Cell corpse engulfment in C. elegans 5
Result
psr-1 encodes a transmembrane protein that is evolutionary
conserved among species 10
psr-1 is important for engulfment of cell corpses during
embryogenesis 11
psr-1 likely acts in engulfing cells to control
cell corpse engulfment 12
psr-1 likely functions upstream of ced-2, 5, 10 and ced-12 13
PSR-1 interacts with CED-5 and CED-12 in vitro 15
cmer is also important for the engulfment of cell corpses during embryogenesis 17
cmer likely acts upstream of ced-2, 5, 10 and ced-12 19
cmer may act with psr-1 in the same pathway to control
cell corpse engulfment 21
Discussion
Phagocytosis of apoptotic cells in mammalian and in C. elegans 22
The function of PSR-1 in phagocytosis 23
The function of cMER in phagocytosis 24
The conserved CED-10/Rac1 GTPase signaling mediated
CED-2/CrkII, CED-5/Dock180, CED-12/ELMO-1 in
cell corpse engulfment 25
Materials and methods 26
Reference 31
Figures and tables 37

Caron, E., and Hall, A. (1998). Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Science 282, 1717-21.
Chung, S., Gumienny, T. L., Hengartner, M. O., and Driscoll, M. (2000). A common set of engulfment genes mediates removal of both apoptotic and necrotic cell corpses in C. elegans [In Process Citation]. Nat Cell Biol 2, 931-7.
Ellis, R., Jacobson, D. M., and Horvitz, H. R. (1991). Genes required for the engulfment of cell corpses during programmed cell death in C. elegans. Genetics 129, 79-94.
Erickson, M., Galletta, B. J., and Abmayr, S. M. (1997). Drosophila myoblast city encodes a conserved protein that is essential for myoblast fusion, dorsal closure, and cytoskeletal organization. J Cell Biol 138, 589-603.
Fadok, V. A., Bratton, D. L., Rose, D. M., Pearson, A., Ezekewitz, R. A., and Henson, P. M. (2000). A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 85-90.
Fadok, V. A., McDonald, P. P., Bratton, D. L., and Henson, P. M. (1998). Regulation of macrophage cytokine production by phagocytosis of apoptotic and post-apoptotic cells. Biochem Soc Trans 26, 653-6.
Fadok, V. A., Voelker, D. R., Campbell, P. A., Cohen, J. J., Bratton, D. L., and Henson, P. M. (1992). Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J Immunol 148, 2207-16.
Giles, K. M., Hart, S. P., Haslett, C., Rossi, A. G., and Dransfield, I. (2000). An appetite for apoptotic cells? Controversies and challenges. Br J Haematol 109, 1-12.
Guermonprez, P., Valladeau, J., Zitvogel, L., Thery, C., and Amigorena, S. (2002). Antigen presentation and T cell stimulation by dendritic cells. Annu Rev Immunol 20, 621-67.
Gumienny, T. L., Brugnera, E., Tosello-Trampont, A. C., Kinchen, J. M., Haney, L. B., Nishiwaki, K., Walk, S. F., Nemergut, M. E., Macara, I. G., Francis, R., Schedl, T., Qin, Y., Van Aelst, L., Hengartner, M. O., and Ravichandran, K. S. (2001). CED-12/ELMO, a novel member of the CrkII/Dock180/Rac pathway, is required for phagocytosis and cell migration. Cell 107, 27-41.
Gumienny, T. L., Lambie, E., Hartwieg, E., Horvitz, H. R., and Hengartner, M. O. (1999). Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline. Development 126, 1011-22.
Hanahan, D., and Weinberg, R. A. (2000). The hallmarks of cancer. Cell 100, 57-70.
Hanayama, R., Tanaka, M., Miwa, K., Shinohara, A., Iwamatsu, A., and Nagata, S. (2002). Identification of a factor that links apoptotic cells to phagocytes. Nature 417, 182-7.
Hasegawa, H., Kiyokawa, E., Tanaka, S., Nagashima, K., Gotoh, N., Shibuya, M., Kurata, T., and Matsuda, M. (1996). DOCK180, a major CRK-binding protein, alters cell morphology upon translocation to the cell membrane. Mol. Cell. Biol. 16, 1770-1776.
Hengartner, M. O. (2001). Apoptosis: corralling the corpses. Cell 104, 325-8.
Henson, P. M., Bratton, D. L., and Fadok, V. A. (2001). The phosphatidylserine receptor: a crucial molecular switch? Nat Rev Mol Cell Biol 2, 627-33.
Hoffmann, P. R., deCathelineau, A. M., Ogden, C. A., Leverrier, Y., Bratton, D. L., Daleke, D. L., Ridley, A. J., Fadok, V. A., and Henson, P. M. (2001). Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J Cell Biol 155, 649-59.
Horvitz, H. R. (1999). Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cancer Res 59, 1701s-1706s.
Jacobson, M. D., Weil, M., and Raff, M. C. (1997). Programmed cell death in animal development. Cell 88, 347-54.
Kiyokawa, E., Hashimoto, Y., Kobayashi, S., Sugimura, H., Kurata, T., and Matsuda, M. (1998). Activation of Rac1 by a Crk SH3-binding protein, DOCK180. Genes Dev 12, 3331-6.
Liu, Q. A., and Hengartner, M. O. (1998). Candidate adaptor protein CED-6 promotes the engulfment of apoptotic cells in C. elegans. Cell 93, 961-72.
Massol, P., Montcourrier, P., Guillemot, J. C., and Chavrier, P. (1998). Fc receptor-mediated phagocytosis requires CDC42 and Rac1. Embo J 17, 6219-29.
Mayer, B. J., Hamaguchi, M., and Hanafusa, H. (1988). A novel viral oncogene with structural similarity to phospholipase C. Nature 332, 272-5.
Nakano, T., Ishimoto, Y., Kishino, J., Umeda, M., Inoue, K., Nagata, K., Ohashi, K., Mizuno, K., and Arita, H. (1997). Cell adhesion to phosphatidylserine mediated by a product of growth arrest-specific gene 6. J Biol Chem 272, 29411-4.
Nobes, C. D., and Hall, A. (1999). Rho GTPases control polarity, protrusion, and adhesion during cell movement. J Cell Biol 144, 1235-44.
Nolan, K. M., Barrett, K., Lu, Y., Hu, K. Q., Vincent, S., and Settleman, J. (1998). Myoblast city, the Drosophila homolog of DOCK180/CED-5, is required in a Rac signaling pathway utilized for multiple developmental processes. Genes Dev 12, 3337-42.
Platt, N., da Silva, R. P., and Gordon, S. (1998). Recognizing death: the phagocytosis of apoptotic cells. Trends Cell Biol 8, 365-72.
Reddien, P. W., and Horvitz, H. R. (2000). CED-2/CrkII and CED-10/Rac control phagocytosis and cell migration in Caenorhabditis elegans. Nat Cell Biol 2, 131-6.
Rubartelli, A., Poggi, A., and Zocchi, M. R. (1997). The selective engulfment of apoptotic bodies by dendritic cells is mediated by the alpha(v)beta3 integrin and requires intracellular and extracellular calcium. Eur J Immunol 27, 1893-900.
Scott, R. S., McMahon, E. J., Pop, S. M., Reap, E. A., Caricchio, R., Cohen, P. L., Earp, H. S., and Matsushima, G. K. (2001). Phagocytosis and clearance of apoptotic cells is mediated by MER. Nature 411, 207-11.
Sulston, J. E., and Horvitz, H. R. (1977). Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev Biol 56, 110-56.
Sulston, J. E., Schierenberg, E., White, J. G., and Thomson, J. N. (1983). The embryonic cell lineage of the nematode Caenorhabditis elegans. Developmental Biology 100, 64-119.
Thompson, C. B. (1995). Apoptosis in the pathogenesis and treatment of disease. Science 267, 1456-62.
Van Aelst, L., and D'Souza-Schorey, C. (1997). Rho GTPases and signaling networks. Genes Dev 11, 2295-322.
Wu, Y. C., Tsai, M. C., Cheng, L. C., Chou, C. J., and Weng, N. Y. (2001). C. elegans CED-12 acts in the conserved CrkII/DOCK180/Rac pathway to control cell migration and cell corpse engulfment. Developmental cell 1, 1-20.
Wu, Y. C., and Horvitz, H. R. (1998). The C. elegans cell corpse engulfment gene ced-7 encodes a protein similar to ABC transporters. Cell 93, 951-60.
Wu, Y. C., and Horvitz, H. R. (1998). C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180 [see comments]. Nature 392, 501-4.
Wyllie, A. H., Kerr, J. F., and Currie, A. R. (1980). Cell death: the significance of apoptosis. Int Rev Cytol 68, 251-306.
Zhou, Z., Caron, E., Hartwieg, E., Hall, A., and Horvitz, H. R. (2001). The C. elegans PH domain protein CED-12 regulates cytoskeletal reorganization via a Rho/Rac GTPase signaling pathway. Dev Cell 1, 477-89.
Zhou, Z., Hartwieg, E., and Horvitz, H. R. (2001). CED-1 Is a tansmembrane receptor that mediates cell corpse engulfment in C. elegans. Cell 104, 43-56.
Zhou, Z., Hartwieg, E., and Horvitz, H. R. (2001). CED-1 is a transmembrane receptor that mediates cell corpse engulfment in C. elegans. Cell 104, 43-56.