All ETDs from UAB

Advisory Committee Chair

Bradley K Yoder

Advisory Committee Members

James F Collawn

John M Parant

Steven M Rowe

Rosa A Serra

Document Type

Dissertation

Date of Award

2016

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Cilia are microtubule based cellular appendages that are present throughout the hierarchy of the animal kingdom. These appendages are utilized for a wide array of functions such as motility in single celled organisms to coordinating complex cellular signaling pathways in more complex organisms. Though these appendages are well conserved, the exact function of cilia in many cell types remains unknown. Recently, cilia are tied to a myriad of developmental diseases and diseases of adult homeostasis collectively referred to as ciliopathies. Dysfunction in cilia results in a wide array of phenotypes ranging from retinal degeneration to polydactyly, cystic kidney disease, and obesity. While it is known that cilia are involved in the development of the phenotypes, the underlying molecular mechanisms remain unknown. Hence, it is essential to study the genes involved in these diseases in model systems such as mouse and zebrafish. In the following thesis, I will document the importance of a gene known as Growth Arrest Specific 8 (GAS8) in motile cilia function and the development of a human disease known as Primary Cilia Dyskinesia (PCD). I show that Gas8 is an essential component of a motile cilia complex known as the Nexin-Dynein Regulatory Complex (N-DRC) and that loss of Gas8 leads to destabilization of the microtubule ring of motile cilia and dyskinetic cilia. Similarly, I will show that Gas8 is a disease causing gene in humans by using the CRISPR/Cas9 system to mimic in mice a known human mutation and show that this mutation is disease causative. Also, I will show that the ciliary transition zone gene Meckel-Grüber 6 (MKS6) is critical for cilia function. Congenital loss of Mks6 leads to embryonic lethality while conditional loss leads to disruptions such as cystic kidneys and retinal degeneration in development and adult homeostasis.

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