Advisory Committee Chair
Bradley Yoder
Document Type
Dissertation
Date of Award
2024
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
As the largest and most dynamic family of GTPases within the mammalian cell, Rabs play an essential role as molecular switches in regulating intracellular vesicular trafficking and serve as significant signaling transducers. Over the last few decades, Rabs have been identified to regulate endocytic, transcytosis, and exocytotic pathways, and mutations in Rabs, or alterations in downstream effectors lead to embryonic lethality and diseases such as cancer and ciliopathies. Ciliopathies are a class of pathologies that result from defects in structure or function of the primary cilia. Primary cilia, found on virtually all mammalian cells, is a microtubule-derived appendage that relies on vesicular trafficking to be assembled and maintained. Several Rab GTPases have been previously identified to regulate the assembly, composition, and/or function of primary cilia. This dissertation explores the role of Rab35 in cilia biology and its impact on embryonic development and post-natal diseases in mice. Using a combination of genetics, bioinformatics, basic cellular biology, and biochemistry, the study reveals that Rab35, initially identified through a bioinformatics algorithm, plays a substantial role in regulating cilia length and is essential for embryonic development. The absence of Rab35 in mice led to developmental and postnatal ciliopathic phenotypes such as hydronephrosis and cholangiocyte hyperplasia. The study also finds that Rab35 affects epithelial cell adherens and tight junction proteins and is involved in maintaining tissue function, specifically in the kidney, ureter, and liver. These findings provide valuable insights into cilia biology, human diseases, and establish a new animal model for further study in the field. Future work will be focused on assessing how Rab35 regulation of ciliary length affects ciliary composition and signaling during development and tissue homeostasis.
Recommended Citation
Clearman, Kelsey Ruth, "Novel Roles Of Rab35 In Development And Disease" (2024). All ETDs from UAB. 3895.
https://digitalcommons.library.uab.edu/etd-collection/3895