Membrane fusion is one of lifes most fundamental processes. Among three major types of membrane fusion events -- intracellular vesicle fusion, virus-cell fusion, and cell-cell fusion -- the latter is the least well understood. Cell-cell fusion is critical for the development and physiology of multicellular organisms and is involved in processes as diverse as fertilization, formation of bone and placenta, myogenesis, immune response, tumorigenesis, and aspects of stem cell mediated tissue repair. Despite the diversity of cell types that undergo fusion, the cellular events involved in this process cell recognition, adhesion, and membrane merger are common to all these cell types, suggesting that shared molecular mechanisms may be used.
My lab uses Drosophila myoblast fusion as a genetic model to understand the general mechanisms of cell-cell fusion. The major questions we address include: How do cells destined to fuse recognize and adhere with each other? How is the fusion signal transduced within a fusing cell? What are the minimal components of the fusion machinery? Using a systematic genetic approach, we have identified a collection of genes required for myoblast fusion. Molecular and biochemical characterizations of these genes and their products have so far revealed a signaling cascade from the transmembrane cell adhesion molecules to the actin cytoskeleton during myoblast fusion.
Our recent cell biological and ultrastructural studies have led to the discovery of an invasive podosome that is required for promoting fusion pore formation. Moreover, we have defined a fusogenic synapseEthat is composed of an asymmetric cell adherence junction with associated vesicle transport/secretion activities at the site of myoblast fusion. Our current effort is directed towards understanding the mechanisms controlling prefusion vesicle trafficking, revealing the ECM protease activity associated with the podosome, and identification of the elusive fusogenic protein that mediates plasma membrane fusion. We are also extending our fly studies to mouse satellite cells to investigate the cellular/molecular mechanisms of satellite cell fusion during mammalian skeletal muscle development.
Publications:
Zhang, S., and Chen, E.H. (2008) Ultrastructural Analysis of Myoblast Fusion in Drosophila. In Cell Fusion, E. H. Chen ed. (the Humana Press Inc., New Jersey).
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Kim, S.*, Shilagardi, K.*, Zhang, S.*, Hong, S.N., Sens, K.L., Bo, J., Gonzalez, G.A., and Chen, E.H. (2007) A Critical Function for the Actin Cytoskeleton in Targeted Exocytosis of Prefusion Vesicles During Myoblast Fusion. Developmental Cell. 12, 571-586.
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Chen, E.H., Grote, E., Mohler, W., and Vignery, A. (2007) Cell-cell fusion. FEBS Letters. 581, 2181-93.
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Chen, E.H., and Olson, E.N. (2005) Unveiling the Mechanisms of Cell-Cell Fusion. Science. 308, 369-373.
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Chen, E.H., and Olson, E.N. (2004) Toward a molecular pathway of myoblast fusion in Drosophila. Trends in Cell Biology. 14, 452-460.
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Chen, E.H., Pryce, B.A., Tzeng J.A., Gonzalez, G.A., and Olson, E.N. (2003) Control of myoblast fusion by a guanine nucleotide exchange factor, Loner, and its effector ARF6. Cell. 114, 751-762.
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Gajewski, K., Wang J., Molkentin, J.D., Chen, E.H., Olson, E.N., and Schulz, R.A. (2003) Requirement of the calcineurin subunit gene canB2 for indirect flight muscle formation in Drosophila. Proc. Natl. Acad. Sci. USA. 100, 1040-1045.
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Chen, E.H., and Olson, E.N. (2001) Antisocial, an intracellular adaptor protein, is required for myoblast fusion in Drosophila. Developmental Cell. 1, 705-715.
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