Revealing membrane dynamics, structure, and function by correlative light and electron microscopy
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All eukaryotic cells use membranes to spatially organize their numerous intracellular processes. These membranes are not just inert barriers. They are compositionally and morphologically dynamic, and their shape and topology are intimately tied to organelle function. Essential processes such as endocytosis, intracellular transport, and inter-organelle communication are all dependent on properly regulating membrane architecture. Conversely, defects in membrane morphology of different organelles have been linked to various human diseases. Yet, the mechanisms that couple membrane architecture to associated cellular functions are poorly understood and challenging to study.
We are addressing these problems by applying state-of-the-art microscopy at multiple scales of resolution, ranging from fluorescence imaging of live cells to electron microscopy of cellular ultrastructure. We have developed novel methods for visualizing the identical structures at both scales, permitting the exploration of rare or transient events. We can reconstruct the 3D membrane ultrastructure of these events and correlate them to the absence or presence of key protein components. We expand this approach to cryo electron tomography to visualize protein structures in their native environment. By combining these microscopy methods with molecular genetic tools, we seek to provide a mechanistic understanding of how membrane architecture intersects with various cellular processes.
Areas of special interest at present relate to the membrane architecture at contact sites between two organelles, and to mitochondrial membrane dynamics. Organelle contact sites are important for communication and exchange of molecules such as Calcium, lipids, and metabolites. In addition, contacts between the endoplasmic reticulum and mitochondria assist in mitochondrial division. Division and fusion dynamics contribute to maintaining the cell’s mitochondrial network. Possible PhD projects on these topics will be discussed during the interviews. The eventual project outline will depend on personal interest and background of the candidate, and will combine cell biology with various modalities of microscopy and image analysis.
Kukulski, W., Schorb, M., Kaksonen, M., and Briggs, J.A. (2012)
Plasma membrane reshaping during endocytosis is revealed by time-resolved electron tomography.
Cell 150, 508-520.
Kukulski, W., Schorb, M., Welsch, S., Picco, A., Kaksonen, M., and Briggs, J.A. (2011)
Correlated fluorescence and 3D electron microscopy with high sensitivity and spatial precision.
J. Cell Biol. 192, 111-119.
Prinz, W. A. (2014)
Bridging the gap: Membrane contact sites in signaling, metabolism, and organelle dynamics.
J. Cell Biol. 205, 759-69.
Mahamid, J., Pfeffer, S., Schaffer, M., Villa, E., Danev, R., Cuellar, L.K., Forster, F., Hyman, A.A., Plitzko, J.M., Baumeister, W. (2016).
Visualizing the molecular sociology at the HeLa cell nuclear periphery.
Science 351, 969-972.