Biophysical Society Thematic Meeting| Padova 2019

Quantitative Aspects of Membrane Fusion and Fission

Poster Abstracts

32-POS Board 32 THE LIFE OF A BETA CELL WITHOUT DYNAMIN Fan Fan 1 ; Yumei Wu 2 ; Natalia Tamarina 3 ; Shawn M Ferguson 2 ; Louis Philipson 3 ; Pietro De Camilli 2 ; Xuelin Lou 1 ; 1 Medical College of Wisconsin, Department of Cell Biology and Neurobiology, Milwaukee, Wisconsin, USA 2 Yale University, School of Medicine, Department of Cell Biology, CNNR program, New Haven, Connecticut, USA 3 University of Chicago, Department of Medicine, Kovler Diabetes Center, Chicago, Illinois, USA We study the molecular basis of vesicle trafficking in neurons and endocrine cells. GWAS studies predict that membrane trafficking defect in pancreatic ß cells lies at the central of diabetes. Here we evaluate the effect of imbalanced membrane trafficking on insulin secretion by fully shutting down dynamin-mediated trafficking. We generated a mouse model (cTKO) that lacks all three mammalian dynamin genes ( DNM 1 , 2 and 3 ) selectively in adult ß cells and examined insulin granule trafficking using multiple sensitive approaches both in vitro and in vivo. Deletion of 3 dynamin genes led to impaired (but not abolished) endocytosis and aberrant clathrin-coated endocytic intermediates. Interestingly, individual insulin granules showed higher mobility and slower fusion kinetics, indicating impaired exocytosis and fusion pore dynamics. Moreover, cTKO mice developed hyperglycemia and glucose intolerance. This work illustrates that dynamin functions in both membrane fission and fusion of dense core vesicles, highlighting a fundamental role of dynamin-mediated trafficking balance in preserving insulin secretion and glucose homeostasis.

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