Date of Award

8-1-2018

Document Type

Dissertation

Degree Name

Ph.D.

Organizational Unit

Biological Sciences

First Advisor

Scott A. Barbee, Ph.D.

Second Advisor

Joseph Angleson

Third Advisor

Cedric Asensio

Fourth Advisor

David Patterson

Fifth Advisor

Michelle Knowles

Keywords

FMRP, Fragile X mental retardation protein, Fragile X syndrome, GW182, MicroRNA, Neuronal granules, Translation repression

Abstract

Fragile X syndrome (FXS) is the most common inherited monogenic cause of intellectual disability. FXS patients exhibit social and language deficits, hyperactivity, seizures, growth abnormalities, macroorchidism, anxiety, and epilepsy. FXS is caused by the transcriptional silencing of the fragile X mental retardation gene 1 (Fmr1), resulting in the loss of the fragile X mental retardation protein (FMRP). FMRP is a selective mRNA binding protein that plays a role in translation repression. Studies suggest that FMRP utilizes the miRNA pathway to repress translation of its target mRNAs through an unknown mechanism. The aim of my thesis is to investigate the mechanism by which FMRP regulates the translation of specific mRNA targets via the miRNA pathway using Drosophila melanogaster as a model system. Here, we demonstrate that FMRP requires the core miRNA-induced silencing complex (miRISC) components, AGO1 and GW182, to mediate translation repression. Moreover, we show that FMRP itself is necessary for miRNAs to repress translation of a reporter mRNA, which suggests an interdependent role of FMRP and miRNA in regulating gene silencing. Finally, our findings elucidate a novel role for GW182 in the maintenance of proper synaptic structure and morphology at the glutamatergic larval neuromuscular junction (NMJ) in an FMRPdependent manner. We propose that FMRP binds to the 3'UTRs of target mRNAs and controls translation of target mRNAs in a GW182-dependent manner. Our data improve current understanding of the normal FMRP function in neurons. We postulate that this could assist in the discovery of novel therapeutic targets to treat FXS and related autism spectrum disorders.

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Rights Holder

Navneeta Kaul

Provenance

Received from ProQuest

File Format

application/pdf

Language

en

File Size

184 p.

Discipline

Molecular biology

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