Elizabeth Chen

Academic Titles: 
Adjunct Professor
410-502-2542

725 N. Wolfe Street, Baltimore, MD 21205

Research Interest: 
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. 

Lab Members:
Research

Cell-cell fusion is critical for the conception, development, and physiology of multicellular organisms. Although cellular fusogenic proteins and the actin cytoskeleton are implicated in cell-cell fusion, it remains unclear whether and how they coordinate to promote plasma membrane fusion. We reconstituted a high-efficiency, inducible cell fusion culture system in the normally nonfusing Drosophila S2R+ cells. Both fusogenic proteins and actin cytoskeletal rearrangements were necessary for cell fusion, and in combination they were sufficient to impart fusion competence.

Selected Publications:
Kim J, Duan R, Jin P, Chen EH. (2015) Mechanisms of myoblast fusion during muscle development. Current Opinion in Genetics and Development. 32, 162-170. [ pdf ]
Kim JH, Ren Y, Ng WP, Li S, Son S, Kee Y, Zhang S, Zhang G, Fletcher DA, Robinson DN, Chen EH. (2015) Mechanical tension drives cell membrane fusion. Developmental Cell 32, 561-73. [ pdf ]
Shilagardi K, Li S, Luo F, Marikar F, Duan R, Jin P, Kim J, Murnen K, Chen EH. (2013) Actin-propelled invasive membrane protrusions promote fusogenic protein engagement during cell-cell fusion. Science 340(6130):359-363. [ link ]
Duan R, Jin P, Luo F, Zhang G, Anderson N, Chen EH. (2012) Group I PAKs function downstream of Rac to promote podosome invasion during myoblast fusion in vivo. Journal of Cell Biology 199(1):169-85. [ link ]
Jin P, Duan R, Luo F, Zhang G, Hong N, Chen EH. (2011) Competition between Blown fuse and WASP for WIP binding regulates the dynamics of WASP-dependent actin polymerization in vivo. Developmental Cell 20:623-638. [ link ]
Sens KL, Zhang S, Jin P, Duan R, Zhang G, Luo F, Parachini L, Chen EH. (2010) An invasive podosome-like structure promotes fusion pore formation during myoblast fusion. Journal of Cell Biology 191, 1013-1027. [ link ]
Kim S, Shilagardi K, Zhang S, Hong S, Sens K, Bo J, Gonzalez GA, Chen EH. (2007). A Critical Function for the Actin Cytoskeleton in Targeted Exocytosis of Prefusion Vesicles during Myoblast Fusion. Developmental Cell. 12, 571-86. [ link ]
Chen EH, Olson EN. (2005). Unveiling the mechanisms of cell-cell fusion. Science 308, 369-373. [ link ]