All ETDs from UAB

Advisory Committee Chair

Michael A Miller

Advisory Committee Members

Bradley K Yoder

P Darwin Bell

Guillero Marques

Eric M Schwiebert

Elizabeth S Sztul

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Cilia are evolutionarily conserved, membrane-bound, microtubule-based organelles found on a diverse array of cell types in eukaryotic organisms. Inherited diseases of cilia protein dysfunction include Nephronophthisis (NPHP), Joubert Syndrome (JBTS), Meckel-Gruber Syndrome (MKS), and Bardet-Biedl Syndrome (BBS). Important insight in the basic cell biological functions of BBS and NPHP proteins has been gained from analysis in the nematode Caenorhabditis elegans. My goal in this dissertation was to model MKS protein function in cilia biology utilizing the powerful genetic malleability of C. elegans. mks-1 and mks-3, the C. elegans homologs of two MKS-associated proteins in humans, were selected for this analysis. MKS-3 is a transmembrane protein of unknown function, and MKS-1 is a protein comprised of an uncharacterized motif called the B9 domain. Because the B9 domain is found in only two other proteins in C. elegans (and most other eukaryotes), the B9 proteins TZA-1 and TZA-2 were also included in this analysis. Lastly, the C. elegans homologs of NPHP proteins NPHP-1 and NPHP-4 were also analyzed in conjunction with the MKS/TZA proteins. Utilizing mutations in each of the genes encoding these proteins, we were able to develop a model in which the MKS/B9 proteins and the NPHP proteins form independent but functionally related complexes at the base of C. elegans cilia. Disruption of either complex alone by genetic mutation did not hinder cilia formation. However, simultaneous disruption of both complexes resulted in severe ciliogenesis defects. This functional requirement of either the MKS/B9 or the NPHP complex for cilia formation indicates that the two protein complexes serve similar yet distinct roles in maintaining cilia homeostasis. In the absence of a functional MKS/B9 complex, transmembrane proteins that normally localized only to the base of cilia (or just outside of the ciliary base) freely accessed the entire ciliary membrane. This data supports a model in which the MKS/B9 complex regulates ciliary membrane composition by selectively holding some transmembrane proteins at the base of cilia while blocking other transmembrane proteins from accessing the cilium. Overall, this dissertation provides insight into the related but distinct functions of MKS/B9 and NPHP proteins in cilia biology.