Vesicular Trafficking of RNA from the Soma to the Germline

Harvard Medical School, Boston MA

Investigators

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Abstract

PROJECT SUMMARY / ABSTRACT Animals have evolved sophisticated systems that allow their many millions of cells to communicate with each other. These systems enable cells and tissues to act in coordination during development and in response to changing environmental conditions. Some cell-to-cell communication is thought to be mediated by extracellular vesicles (EVs), phospholipid membrane-enclosed vesicles found in animal circulatory systems. Some EVs contain RNA and these EVs are referred to as RNA EVs. RNA encapsulated within EVs can be biologically active. For instance, EVs can traffic mRNAs from one tissue culture cell to other tissue culture cells and, once internalized, these mRNAs can be translated. Thus, RNA EVs may be important mediators of cell-cell communication in animals. dsRNA-mediated gene silencing (termed RNA interference, RNAi) is systemic in the nematode C. elegans: dsRNAs expressed in one somatic cell can move to other somatic cells. Interestingly, RNAi is also heritable in C. elegans: dsRNAs can be trafficked from somatic cells to germ cells (termed RNAi inheritance). RSD-3/CLINT is a conserved membrane trafficking factor, which is thought to contribute directly to vesicle formation in mammals. In C. elegans, I have shown that RSD-3 is required for the movement of silencing RNAs from somatic cells to germ cells. I have also shown that RSD-3 coats intracellular vesicles that are exocytosed from somatic cells and deposited in the germline. I hypothesize that RSD-3 EVs deliver RNA payloads from the soma to the germline during the normal course of reproduction. My proposed experiments are designed to test this model, identify endogenous RNAs trafficked between cells in vivo, and explore the mechanism by which RNA EVs are formed and mobilized. My research is important because it explores two poorly understood biological processes: RNA-based intercellular communication and RNA-directed epigenetic inheritance. RNA EVs are clearly present in the circulatory fluids of most animals but their in vivo function, if any, is not known. I have developed a system to study the how and why of RNA EVs in an animal model. To date, I have identified two factors likely required for RNA EV function in C. elegans. Both of these factors are conserved in mammals, hinting that my findings in C. elegans may help us understand how and why RNAs move between cells in all animals. Therefore, my work exploring how RNA EVs are produced and what function they have in vivo may suggest ways to clinically manipulate RNA EVs in order to intervene in human disease.