Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Collaborative Specialization

Developmental Biology

Supervisor

Kramer, Jamie M.

2nd Supervisor

Daley, Mark J.

Co-Supervisor

Abstract

Over the lifetime of an organism, neurons must establish, remodel, and maintain precise connections in order to form neural circuits that are required for proper nervous system functioning. Disruptions in these processes can lead to neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorder. Mutations in genes encoding subunits of the SWI/SNF chromatin remodeling complex have been implicated in ID, yet the role of this complex in neurons is poorly understood. In this project, I established cell-type specific methods to examine the effect of SWI/SNF subunit knockdowns on gene transcription and chromatin structure in the memory-forming neurons of the Drosophila mushroom body (MB) during periods of neuronal remodeling and experience-dependent synaptic plasticity. Combining transcriptome and epigenome profiling of MB neurons at the onset of pupation revealed that the SWI/SNF complex is critical for regulating genes that are essential to MB γ neuron axon pruning during pupation. These genes include the steroid hormone receptor EcR-B1 and members of the ubiquitin proteasome system. Additionally, the SWI/SNF complex was shown to have a stage-specific effect in regulating chromatin accessibility and transcription of genes required during a critical window of experience-dependent synaptic plasticity in juvenile adult flies. Among these were several genes involved in response to stimulus and axon guidance, including: forked end, Calmodulin, and Dichaete, and the gene encoding an actin-binding protein involved in brain development, Ciboulot. This study investigates the neuron-specific gene regulatory role of the SWI/SNF complex. These findings reveal specific roles for the SWI/SNF complex in regulating distinct processes in post-mitotic neurons and provide the groundwork in understanding the effect of chromatin regulation in SWI/SNF-related ID.

Summary for Lay Audience

Throughout the lifetime of an organism, neurons must establish, remodel, and maintain precise connections in order to form neural circuits that are required for proper nervous system functioning. Disruptions in these processes can lead to neurodevelopmental disorders such as intellectual disability (ID) and autism spectrum disorder. Mutations in genes encoding members of the SWI/SNF chromatin remodeling complex have been associated with ID, suggesting a link between DNA organization and brain wiring. The role of the SWI/SNF complex in neurons in neurons, however, is poorly understood. In this project, I examined the effect of SWI/SNF knockdown on gene expression and chromatin structure in the Drosophila mushroom body (MB) – the learning and memory centre of the fly brain. During pupation, the MB undergoes neuronal remodeling and also undergoes a period of experience-dependent brain wiring in the early hours of adult life. In this thesis, I find that the SWI/SNF complex is critical in regulating the expression of genes involved in MB neuron remodeling during pupation, and that the SWI/SNF complex targets genes important for MB development in the juvenile adult. These findings reveal new and specific roles for the SWI/SNF complex in regulating distinct processes governing neurodevelopment and provides the groundwork in understanding the effect of chromatin structure in SWI/SNF-related ID.

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