Date of Award

Spring 2012

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biological Sciences

First Advisor

Allison L. Abbott

Second Advisor

James T. Anderson

Third Advisor

Stephen H. Munroe

Abstract

microRNAs (miRNAs) are approximately 22 nucleotide non-coding RNAs that function to repress genes by binding to complementary sites in target mRNAs and play critical roles in development and disease. It is predicted that more than 60% of human genes are regulated by miRNAs, however, little is known about the individual functions of miRNAs. I used the nematode worm, Caenorhabditis elegans, as a model to identify developmental processes and pathways regulated by conserved miRNAs. Genetic examination of miRNA function is hindered by lack of obvious phenotypes attributed to loss of individual miRNA genes. Phenotypes attributable to loss of individual miRNA genes were identified by examining worms mutant for individual miRNA genes and alg-1, which encodes an Argonaute protein that functions in the miRNA pathway in C. elegans. This analysis identified functions for 80% of miRNA genes examined. miRNAs were found to regulate diverse processes, including embryonic development, directional migration of the gonad, and developmental timing. The goal of the second half of this study was to determine the mechanism whereby loss of members of the mir-51 miRNA family suppresses the developmental timing defects of alg-1 mutant worms. Genetic evidence indicates the mir-51 family regulates the L2 to L3 transition through regulation of hbl-1 expression. Interestingly, the mir-51 family genetically interacts in pathways regulated by the let-7 and miR-35 families, as well as lsy-6, miR-240/786, and miR-1. Evidence herein indicates that the mir-51 family does not regulate these pathways through miRNA biogenesis or activity. Instead it is possible that the miR-51 family regulates multiple targets in diverse developmental pathways.

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