Graduation Date

Summer 8-17-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmacology and Experimental Neuroscience

First Advisor

Woo-Yang Kim

Abstract

Intellectual disability (ID) and autism spectrum disorder (ASD) affect between one and three percent of the global population. These disorders represent a significant emotional and financial burden for affected individuals and their families. Treatment for these conditions remains limited because many of the key molecular factors and associated pathogenic mechanisms are still poorly understood.

In this report we examine two genes related to ASD and ID, AT-rich interactive domain-containing protein 1B (ARID1B) and Microtubule-actin crosslinking factor 1 (MACF1). ARID1B is a subunit of the mammalian BRG1/BRM associated factor (BAF) chromatin-remodeling complex, which broadly regulates gene expression. ARID1B also interacts with the transcription factor β-catenin, which regulates neurogenesis. Haploinsufficiency of ARID1B causes ID and ASD and mouse models of Arid1b haploinsufficiency exhibit abnormal cognitive and social behaviors and have fewer GABAergic interneurons. MACF1 is a member of the spektraplakin family of proteins and is responsible for regulating microtubule and actin interaction and dynamics. As such, MACF1 plays a role in many cellular processes, such as migration and proliferation. MACF1 is a candidate gene for 1p34.2-p34.3 deletion syndrome, a chromosomal deletion disorder characterized by a greatly increased risk for autism and neurodevelopmental delay. We developed conditional knockout mice for both Arid1b and Macf1 in order to better delineate their respective roles in brain development and mouse behavior.

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