Date of Award

Spring 5-2021

Level of Access Assigned by Author

Open-Access Dissertation

Language

English

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Susan L. Ackerman

Second Committee Member

Robert Burgess

Third Committee Member

Jeffrey Chuang

Additional Committee Members

Wayne Frankel

Dustin Updike

Abstract

The process of translation, which refers to decoding genetic information from mRNA to protein, is vital for all cellular function. Translational fidelity starts at the level of aminoacylation of transfer RNAs (tRNA). This reaction is catalyzed by aminoacyl tRNA synthetases where each amino acid is transferred to its corresponding cognate tRNA. Because tRNAs harbor the anticodon sequence to decodes a particular mRNA codon, the specific aminoacylation of the tRNA with a cognate amino acid establishes the rules of decoding genetic code into proteins. Aminoacylated tRNAs are then delivered to ribosomes, where ribosomes in a highly organized manner need to accurately translate the mRNA into protein.

Because of the complexity of translation, errors may occur during translation and pathways have evolved to mitigate errors and the production of potentially toxic byproducts during translation. However, little is known about the in vivo defects that arise in the absence of these quality control pathways. The outlined studies in this dissertation utilize mouse genetics to identity and interrogate quality control pathways that regulate translational fidelity in the nervous system. These studies reveal that defects in translation through impairment of quality control pathways are deleterious for neuronal homeostasis but seemingly act in a cell-type specific manner and/or

are critical either during or post neurodevelopment. Importantly, the apparent selectivity of defects in translation is influenced by cellular context, changes in the translational landscape and additional pathways that function linear or in parallel.

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