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Elizabeth Chen - Associate Professor
Molecular Biology & Genetics

725 N. Wolfe Street
818 PCTB
Baltimore, MD 21205

Office: 410-502-2542
Fax: 410-502-3295

echen@jhmi.edu

Assistant:
Mechanisms of cell-cell fusion in development and disease
The Chen lab studies mechanisms underlying cell-cell fusion, a fundamental cellular process in the conception, development and physiology of multicellular organisms. We approach this question using a multifaceted approach including genetics, molecular biology, biochemistry, biophysics, live imaging, super-resolution microscopy and electron microscopy. Starting with a forward genetic screen in Drosophila, we have identified multiple evolutionarily conserved core components of the myoblast fusion signaling cascade, and, more importantly, discovered a novel cellular mechanism underlying myoblast fusion. We show that myoblast fusion is an asymmetric process in which one cell invades its fusion partner using actin-propelled membrane protrusions to promote fusion pore formation. Building on insights we learned from myoblast fusion in vivo, we have reconstituted high-efficiency cell-cell fusion in an otherwise non-fusogenic, non-muscle cell line and uncovered a previously unrecognized function for the actin-propelled membrane protrusions in fusogen engagement. Similar actin-based membrane protrusions have since been observed in the fusion of mammalian muscle and non-muscle cells, suggesting that invasive membrane protrusions are used as a conserved and universal mechanism to promote cell-cell fusion. Furthermore, we have discovered a mechanosensory response in the receiving fusion partner and demonstrated that mechanical tension is a driving force for cell-cell fusion. Our work to date has established a biophysical framework for understanding cell-cell fusion – the interplay between the pushing forces and the resisting forces from the two fusion partners at the fusogenic synapse brings the apposing cell membranes into close proximity to facilitate fusogen engagement and membrane fusion. This new conceptual framework has fundamentally changed our understanding of cell-cell fusion and has become a widely accepted paradigm in the field. Current work in the Chen lab aims to address major unanswered questions in cell-cell fusion, including the identification of the elusive myoblast fusogen and investigating the function of lipids and curvature-binding proteins in cell-cell fusion. We are also interested in understanding how mechanical stimuli are transduced from cell membrane to the actomyosin network and how cell-cell fusion is regulated in vertebrate muscle development and regeneration.
Relevant Publications:
Kim, JH, Duan, R, Jin, P, and Chen, EH (2015) Mechanisms of myoblast fusion during muscle development. Curr. Opin. Genet. Dev. 32, 162-170.
 
Kim, J.H., Ren, Y., Ng, W.P., Li, S., Son, S., Kee, Y., Zhang, S., Zhang, G., Fletcher, D.A., Robinson, D.N., and Chen, EH (2015) Mechanical tension drives cell membrane fusion. Dev. Cell  32, 561-73.
 

Shilagardi, K, Li, S, Luo, F, Marikar, F, Duan R, Jin, P, Kim, J, Murnen, K, and Chen, EH (2013) Actin-propelled invasive membrane protrusions promote fusogenic protein engagement during cell-cell fusion. Science 340, 359-363.
Pubmed Abstract

Duan, R, Jin, P, Luo, F, Zhang, G, Anderson, N. and Chen, EH (2012) Group I PAKs function downstream of Rac to regulate podosome invasion during myoblast fusion in vivo. J. Cell Biol.199, 169-85.
Pubmed Abstract

Jin, P, Duan, R, Luo, F, Zhang, G, Hong, N, and Chen, EH (2011) Competition between Blown Fuse and WASP for WIP binding regulates the dynamics of WASP-dependent actin polymerization in vivo. Dev. Cell 20, 623-638.
PubMed Abstract

Sens, KL, Zhang, S, Jin, P, Duan, R, Zhang, G. Luo, F, Parachini, L, and Chen, EH (2010) An invasive podosome-like structure promotes fusion pore formation during myoblast fusion. J. Cell Biol. 191, 1013-1027.
PubMed Abstract

Kim, S. Shilagardi, K, Zhang, S, Hong, SN, Sens, KL, Bo, J, Gonzalez, GA, and Chen, EH (2007) A critical function for the actin cytoskeleton in targeted exocytosis of prefusion vesicles during myoblast fusion. Dev. Cell 12, 571-586.
PubMed Abstract

Chen, EH, and Olson, EN (2005) Unveiling the mechanisms of cell-cell fusion. Science 308, 369-373.
PubMed Abtract

Graduate Program AffiliationsBiochemistry, Cellular & Molecular Biology (BCMB)
Cellular and Molecular Medicine (CMM)

 

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