Date of Award

2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology

First Advisor

Alicia Ebert

Second Advisor

Christopher Francklyn

Abstract

Histidyl-tRNA Synthetase (HARS) is a member of the family of enzymes that are responsible for attaching specific amino acids to their corresponding tRNA molecules. This function is critical for accurate and efficient protein synthesis and therefore is required in every cell of an organism. Interestingly, there are a growing number of tissue-specific disorders associated with mutations in genes for this family. For example, mutations in HARS have been associated with three different genetic disorders. The tissue most commonly affected in these disorders is nervous tissue and symptoms range from peripheral neuropathy to severe cognitive impairment. The bias towards nervous system defects suggests that these ubiquitous proteins may be particularly important for neuronal development and maintenance.

In order to better understand the relationship between HARS and the nervous system, we set out to establish an animal model to study its function in an organismal context. We used a gene knock-down approach to investigate HARS’ influence on zebrafish embryonic development. Our research revealed that neuronal tissues have a higher sensitivity to levels of HARS expression. We found that ubiquitously knocking down HARS expression caused neuronal progenitor cells, specifically those of the retina, to undergo cell cycle arrest and apoptosis. Previous research had indicated that HARS and other members of the aminoacyl-tRNA synthetase family are important for cell proliferation and survival, but our in vivo experiments suggest that this role may be more important in nervous tissues than others. Furthermore, these findings provide valuable insight into HARS-related human disease and lay the groundwork for future studies on the molecular etiology of these phenotypes.

Language

en

Number of Pages

156 p.

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