The Role of Dynamin in Cell-Cell Fusion

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dc.contributor.advisorRobinson, Doug
dc.contributor.committeeMemberSeydoux, Geraldine
dc.contributor.committeeMemberAndrew, Debbie
dc.contributor.committeeMemberMachamer, Carolyn
dc.contributor.committeeMemberMatunis, Erika
dc.creatorGerassimov, Nathalie
dc.creator.orcid0000-0001-5505-7993
dc.date.accessioned2019-10-30T23:54:11Z
dc.date.available2019-10-30T23:54:11Z
dc.date.created2019-08
dc.date.issued2019-04-11
dc.date.submittedAugust 2019
dc.date.updated2019-10-30T23:54:11Z
dc.description.abstractMyoblast fusion leads to the formation of multinucleated muscle fibers and is essential for muscle development and regeneration. Drosophila embryonic muscle development has been an instrumental in vivo system to uncover evolutionarily conserved cellular and molecular mechanisms of myoblast fusion. Work from our lab has shown that myoblast fusion is promoted by a cell type-specific, F-actin-enriched podosome-like structure (PLS) that invades the apposing fusion partner with multiple finger-like protrusions at the fusogenic synapse. Here, we shown that the conserved large GTPase Dynamin (Dyn), best known for its function in endocytosis, is a critical component of myoblast fusion in vivo. Interference with Dyn function during myoblast fusion using two different temperature-sensitive alleles of Drosophila Dyn, shibire^ts (shi^ts), leads to a severe myoblast fusion defect, which can be rescued by overexpressing wild-type Dyn. Furthermore, RNAi knockdown of Dyn in cultured cells that are induced to fuse also results in a fusion defect, suggesting a general role for Dyn in cell-cell fusion. We show that Dyn is enriched within the F-actin foci at the fusogenic synapse in wild-type embryos and that the F-actin foci exhibit abnormal morphology in shi^ts mutant embryos at restrictive temperature, indicating a function of Dyn in organizing these actin-enriched structures. Interestingly, electron microscopy analysis revealed no endocytic vesicles at the fusogenic synapse where Dyn is enriched in wild-type embryos, and no collared pits indicative of blocked endocytosis are observed at the fusogenic synapse in shi^ts mutant embryos at restrictive temperature, suggesting that endocytosis may not play a direct role in myoblast fusion. Together, our findings strongly support a novel endocytosis-independent function of Dyn in regulating F-actin organization during cell-cell fusion.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://jhir.library.jhu.edu/handle/1774.2/61931
dc.language.isoen_US
dc.publisherJohns Hopkins University
dc.publisher.countryUSA
dc.subjectMyoblast fusion
dc.subjectCell-cell fusion
dc.subjectDynamin
dc.subjectDrosophila
dc.subjectS2R+ cells
dc.titleThe Role of Dynamin in Cell-Cell Fusion
dc.typeThesis
dc.type.materialtext
thesis.degree.departmentMolecular Biology and Genetics
thesis.degree.disciplinenot listed
thesis.degree.grantorJohns Hopkins University
thesis.degree.grantorSchool of Medicine
thesis.degree.levelDoctoral
thesis.degree.namePh.D.
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