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Integration of nutritional status with germline proliferation: characterizing the roles of NHR-88 and NHR-49 in the C. elegans gonad

Brooks, Alison (2011) Integration of nutritional status with germline proliferation: characterizing the roles of NHR-88 and NHR-49 in the C. elegans gonad. PhD thesis, Fred Hutchinson Cancer Research Center / University of Washington.

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As organisms cycle between feeding and fasting, they must balance nutritional input with energy expenditures such as reproduction, growth, and repair. To achieve the proper equilibrium, these processes must be tightly regulated, requiring that nutritional status be communicated to all tissues. Lipid-responsive transcription factors called nuclear receptors are key to this transmission of information. Despite a growing knowledge of nuclear receptors, one significant question that remains is how this class of proteins integrates an environmental signal into an organismal response. I have chose to address this question using the nematode C. elegans, in which the nuclear receptor NHR-49 protein levels, as demonstrated by toxicity of multiple nhr-49 rescue constructs. Since the presence of genomic regions including the 3’UTR ameliorates this toxicity, I propose that miRNAs may be involved in titration of NHR-49 levels. To elucidate this involvement, I focused my studies on the two miRNAs predicted to target nhr-49: mir-243 and mir-797. Although I was unable to define the requirement for these miRNAs in fed animals, this research lead me to the establishment of a role for both mir-243 and mir-797 in recovery from the NHR-49 regulated fasting response, adult reproductive diapauses (ARD). Additionally, my work implicated another nuclear receptor, NHR-88, in ARD entry and recovery. I also found that a mutation in nhr-88 sythetically interacts with two other alleles: cyp-35a5(ok1985) and the as-yet unidentified fhc10. Together these genes regulate the size of the mitotically proliferating population in the germline, fecundity, fat metabolism, and lifespan, possibly in response to a dihomo-gamma-linolenic acid-derived ligand. This newly defined network provides a model for studying nuclear receptor-driven transmission of environmental signals throughout the organism. Finally, identification of three factors with selective ARD phenotypes make this diapauses a more viable tool for studying conserved processes such as stem cell maintenance and protective autophagy during starvation.

Item Type: Thesis (PhD)
Subjects: Cellular and Organismal Processes > Metabolism
Molecules > RNA > miRNA
Cellular and Organismal Processes > Genetic processes > Transcription
Depositing User: Craig Johansen
Date Deposited: 01 Mar 2012 18:31
Last Modified: 16 Sep 2015 07:17

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