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Determining the physiological and genetic mechanisms of exophergenesis in Caenorhabditis elegans
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Guasp, Ryan James. Determining the physiological and genetic mechanisms of exophergenesis in Caenorhabditis elegans. Retrieved from https://doi.org/doi:10.7282/t3-r1gw-3e05

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TitleDetermining the physiological and genetic mechanisms of exophergenesis in Caenorhabditis elegans
NameGuasp, Ryan James (author); Driscoll, Monica (chair); Grant, Barth D (member); Zahn, Jeffrey D (member); Barr, Maureen M (member); Rutgers University; School of Graduate Studies
Date Created2022
Other Date2022-05 (degree)
SubjectCellular biology, Molecular biology, Genetics, Aggregate, Exopher, Homeostasis, Neurodegeneration, Neuron, Vesicle
Extent220 pages : illustrations
DescriptionMaintaining homeostasis is critical for all organisms. In this work, I describe a new cellular homeostasis pathway in C. elegans, called exophergenesis, which entails the extrusion of large, membrane-bound extracellular vesicles, capable of expelling large volumes of cytoplasm including aggregated proteins and whole organelles. The contents of exophers are transferred to neighboring cells where they appear to be broken down in a process of trans-cellular degradation. Exophers are characterized by an ability to remain attached to cells that produced them, via a thin filament resembling a nanotube, that allows for transfer of material between soma and exopher compartments. Exophergenesis occurs in a distinct temporal pattern, and can be produced in response to myriad physiological, genetic and pharmacological stressors, which are detailed here. Several genetic pathways are required for the upregulation of exophergenesis in response to fasting stress. Two MAPK signaling cascades, EGF signaling from LIN-3 ligand and LET-23 receptor binding, and FGF signaling from EGL-17 ligand and EGl-15 receptor which converge on downstream MPK-1 and MEK-2 kinases are required. A nutrient sensing pathway requiring MTOR subunit mdt-15, transcription factors cbp-1 and sbp-1, and downstream target fatty acid synthase gene fasn-1 are also required for exophergenesis in response to fasting.
Lastly, the influence of the C. elegans germline in the production of exophers is explored. Exophers begin occurring at the onset of reproductive adulthood, and several embryonic lethal genes including pod-1 and cbd-1 are able to completely abrogate exophergenesis in most cases. Genetic knockdown of eggshell genes perm-2 and perm-4 can enhance exopher production. Expression of cbd-1 is needed in the germline and expression of perm-2 and perm-4 is needed in the somatic gonad showing a complex, multi-tissue signaling cascade is at play, ultimately affecting the proteostasis decisions in the distal mechanosensory neurons. Exophergenesis is a sexually dimorphic process and the pattern of male C. elegans exopher production is characterized. The nature of the hermaphrodite germline signal, whether chemical or physical or a combination of both, is considered. Recent discoveries of exophers occurring in other C. elegans tissues and in mammals are reviewed. Further investigation into exophers in C. elegans is warranted due to the potential relevance of exophergenesis to human pathology.
NotePh.D.
NoteIncludes bibliographical references
Genretheses
Persistent URLhttps://doi.org/doi:10.7282/t3-r1gw-3e05
LanguageEnglish
CollectionSchool of Graduate Studies Electronic Theses and Dissertations
Organization NameRutgers, The State University of New Jersey
RightsThe author owns the copyright to this work.
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