All ETDs from UAB

Advisory Committee Chair

Bradley K Yoder

Advisory Committee Members

Robert A Kesterson

Michael A Miller

David A Schneider

Elizabeth S Sztul

Bradley K Yoder

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Cilia and flagella are microtubule based organelles found on nearly every cell type in the mammalian body. Flagella have an essential role in sperm locomotion and reproduction, while motile cilia have a known role in fluid movement in the brain, lungs, and portions of the female reproductive tract. While the role of most primary cilia remained unknown for decades, they are now recognized as being essential to mammalian development, renal homeostasis, and satiety, just to name a few. Because of their widespread presence and importance, dysfunction of cilia and flagella can lead to a variety of human diseases, collectively referred to as ciliopathies. These diseases present with a variety of symptoms including developmental defects, infertility, and obesity, reflecting the various functions of cilia and flagella. Studying the pathogenesis and molecular mechanisms of these diseases in humans is often made difficult due to both practical and ethical issues, and as such animal models are often used to determine the function of genes and proteins that are linked to human ciliopathies, in addition to elucidating what signaling pathways are being affected. In particular, the mouse has proven to be an excellent model organism for studying ciliopathies. Being mammals, their physiology often closely matches that of humans, and the creation of cilia mutant mice has provided valuable information on how cilia are built, maintained, and what role they play in body. In the following thesis, I will report my findings documenting a previously uncharacterized mammalian cilia gene, Cluap1. I will show that Cluap1 mutant mice have phenotypes closely resembling that of mice with mutations in known Meckel-Gruber syndrome genes, a perinatally lethal ciliopathy. Similarly, my research into Ccdc42 has uncovered that loss of this gene causes azoospermia and male infertility in mice due to dysfunctional flagella assembly. This gene is highly conserved and is thus a good candidate loci that may be involved in infertility in human males. Finally, I will also discuss my work into the link between cilia and obesity. Previous studies have indicated the hyperphagia/obesity phenotype associated with cilia dysfunction is due to the development of leptin resistance. However, I show that a defect in leptin signaling is not the primary cause of the obesity phenotype, but instead involves a currently unknown mechanism.

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