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    Identification and Characterization of MicroRNA Modulators in Caenorhabditis Elegans: A Dissertation

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    Authors
    Ren, Zhiji
    Faculty Advisor
    Victor Ambros, PhD
    Academic Program
    Interdisciplinary Graduate Program
    UMass Chan Affiliations
    Program in Molecular Medicine
    Document Type
    Doctoral Dissertation
    Publication Date
    2016-02-26
    Keywords
    Dissertations, UMMS
    Caenorhabditis Elegans
    MicroRNAs
    3' Untranslated Regions
    RNA-Binding Proteins
    RNA Interference
    Caenorhabditis elegans Proteins
    Caenorhabditis Elegans
    MicroRNAs
    3' Untranslated Regions
    RNA-Binding Proteins
    RNA Interference
    Caenorhabditis elegans Proteins
    Developmental Biology
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    Abstract
    MicroRNAs (miRNAs) are endogenous non-coding small RNAs that posttranscriptionally regulate gene expression primarily through binding to the 3’ untranslated region (3’UTR) of target mRNAs, and are known to play important roles in various developmental and physiological processes. The work presented in this thesis was centered on understanding how Caenorhabditis elegans miRNAs are modulated by genetic, environmental, or physiological factors and how these small RNAs function to maintain the robustness of developmental processes under stressful conditions. To identify modulators of the miRNA pathway, I developed sensitized genetic backgrounds that consist of a panel of miRNA gene mutants and miRNA biogenesis factor mutants with partially penetrant phenotypes. First, I found that upon infection of Caenorhabditis elegans with Pseudomonas aeruginosa, an opportunistic pathogen of diverse plants and animals, let-7 family miRNAs are engaged in reciprocal regulatory interactions with the p38 MAPK innate immune pathway to maintain robust developmental timing despite the stress of pathogen infection. These let-7 family miRNAs, along with other developmental timing regulators, are also integrated into innate immune regulatory networks to modulate immune responses. Next, I demonstrated that loss-of-function mutations of Staufen (stau-1), a double-stranded RNA-binding protein, increase miRNA activity for several miRNA families, and this negative modulation of Staufen on miRNA activity acts downstream of miRNA biogenesis, possibly by competing with miRNAs for binding to target mRNA 3’UTRs. In summary, these studies provide a better understanding on how miRNAs are modulated by various environmental and cellular components, and further support the role of the miRNA pathway in conferring robustness to developmental processes under these perturbations.
    DOI
    10.13028/M22G6V
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32207
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/M22G6V
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      Watson, Emma (2015-09-17)
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      Age-related Changes in the Neuronal Architecture of Caenorhabditis Elegans: A Dissertation

      Khandekar, Anagha (2015-10-16)
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      A cohort of Caenorhabditis species lacking the highly conserved let-7 microRNA

      Nelson, Charles J.; Ambros, Victor R. (2021-04-23)
      The let-7 gene encodes a highly conserved microRNA with critical functions integral to cell fate specification and developmental progression in diverse animals. In Caenorhabditis elegans, let-7 is a component of the heterochronic (developmental timing) gene regulatory network, and loss-of-function mutations of let-7 result in lethality during the larval to adult transition due to misregulation of the conserved let-7 target, lin-41. To date, no bilaterian animal lacking let-7 has been characterized. In this study, we identify a cohort of nematode species within the genus Caenorhabditis, closely related to C. elegans, that lack the let-7 microRNA, owing to absence of the let-7 gene. Using Caenorhabditis sulstoni as a representative let-7-lacking species to characterize normal larval development in the absence of let-7, we demonstrate that, except for the lack of let-7, the heterochronic gene network is otherwise functionally conserved. We also report that species lacking let-7 contain a group of divergent let-7 paralogs-also known as the let-7-family of microRNAs-that have apparently assumed the role of targeting the LIN-41 mRNA.
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