Functional genomic analysis of myelin membrane growth in oligodendrocytes
Final Report Abstract
Myelin-forming glia are highly polarized cells that synthesize as an extension of their plasma membrane, a multilayered myelin membrane sheath, with a unique protein and lipid composition. This process leads to the generation of myelin and is associated with dramatic changes in plasma membrane structure and composition. In our project we studied the mechanisms underlying the formation of myelin in the central nervous system. To function as an electrical insulator, myelin is composed of an unusually high amount of tightly organized lipids and a small set of few low-molecular weight proteins. Due to its simple molecular composition, its high abundance and its implication in diseases it has served as a model membrane for a long time. However, the mechanisms of how myelin acquires its unique composition have remained obscure. In our project we uncovered a previously unknown diffusion barrier in myelin formed by the myelin basic protein (MBP). We find that MBP forms a size-selective barrier in cytoplasmic space of myelin, which prevents the diffusion of most soluble and membrane proteins into the myelin sheath. This barrier acts as a molecular sieve restricting the passage of proteins with large cytoplasmic domains into the myelin-membrane sheets. Consequently, our study demonstrates that a simple physical filtering mechanism regulates protein to lipid ratio in myelin. We show that the binding of MBP to two membranes drives self-association and a phase-transition into high-order complexes. Furthermore, we have studied the mechanism underlying the wrapping of the myelin membrane around the axon. In summary our projects has provided new insights of myelin acquires its unique shape and molecular composition in the central nervous system.
Publications
-
(2011) A Size Barrier Limits Protein Diffusion at the Cell Surface to Generate Lipid-Rich Myelin- Membrane Sheets. Dev Cell. Sep 13;21(3):445-56
Aggarwal S, Yurlova L, Snaidero N, Reetz C, Frey S, Zimmermann J, Pähler G, Janshoff A, Friedrichs J, Müller DJ, Goebel C, Simons M
-
(2013) A global in vivo Drosophila RNAi screen identifies a key role of ceramide phosphoethanolamine for glial ensheathment of axons. PloS Genetics, Dec;9(12):e1003980
Ghosh A, Kling T, Snaidero N, Sampaio JL, Shevchenko A, Schulz JB, Voigt A, Simons M
-
(2013). Loss of electrostatic cell-surface repulsion mediates myelin membrane adhesion and compaction in the central nervous system. Proc Natl Acad Sci USA Feb 19;110(8):3143-8
M. Bakhti, N. Snaidero, D. Schneider , S. Aggarwal , W. Möbius, A. Janshoff, M. Eckhardt, K.A. Nave, M. Simons
-
(2013). Myelin Membrane Assembly Is Driven by a Phase Transition of Myelin Basic Proteins Into a Cohesive Protein Meshwork. PLoS Biology Jun;11(6):e1001577
Aggarwal S, Snaidero N, Pähler G, Frey S, Sànchez S, Zweckstetter M, Janshoff A, Weil MT, Schaap IA, Görlich D, Simons M
