Cilia are cellular organelles that are important for human development, organ function, and sensation. Defects in cilia formation or function results in devastating human diseases or ciliopathies, including autosomal dominant polycystic kidney disease (ADPKD). ADPKD affects 1/400-1000 individuals, often resulting in end- stage renal disease. In humans, mutations in the polycystin-1 or polycystin-2 receptor-channel complex cause ADPKD. Despite the profound medical importance of cilia in human health, how cilia are specialized in form and function remains poorly understood. This proposed research is focused on uncovering fundamental principals of cilia biology not possible in human studies or easily studied in vertebrate model systems. C. elegans is a transparent, multicellular animal with specialized sensory cilia, features that enable in vivo imaging that is unprecedented in its simplicity and reproducibility. We have developed the tools and reagents to study polycystin localization and function in C. elegans. We will employ genetic, molecular, imaging, biochemical, and electrophysiological approaches to address three specific aims. First, we will dissect polycystin signaling pathways. Next, we will determine the molecular details of mechanisms regulating polycystin localization, focusing on the roles of phosphoinositides and tubulin post-translational modifications. Finally, we will identify new genes regulating PKD-2 localization using transgenic animals that are hypersensitive to neuronal RNAi. This multidisciplinary approach will provide a comprehensive picture of the molecules that influence polycystin channel assembly and trafficking, and will provide critical insight to ciliary receptor trafficking in general. Thus these studies will have important implications in human diseases such as ADPKD in which cilia play an important and central role.
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic diseases, affecting 1/400-1000 individuals, and having no treatment or cure. Several human genetic disorders, including ADPKD, share two common features: ciliary localized gene products and kidney cysts. Given that it is prohibitively difficult in humans to study the connection between ciliary protein function, localization, and disease, alternative experimental systems are necessary. In C. elegans it is feasible to study the roles of human disease gene homologs in cilia formation, morphogenesis, and signaling. This proposal is aimed at understanding the molecular mechanisms controlling the subcellular trafficking of the C. elegans ADPKD gene products.
|Barr, Maureen M; García, L Rene; Portman, Douglas S (2018) Sexual Dimorphism and Sex Differences in Caenorhabditis elegans Neuronal Development and Behavior. Genetics 208:909-935|
|Silva, Malan; Morsci, Natalia; Nguyen, Ken C Q et al. (2017) Cell-Specific ?-Tubulin Isotype Regulates Ciliary Microtubule Ultrastructure, Intraflagellar Transport, and Extracellular Vesicle Biology. Curr Biol 27:968-980|
|O'Hagan, Robert; Silva, Malan; Nguyen, Ken C Q et al. (2017) Glutamylation Regulates Transport, Specializes Function, and Sculpts the Structure of Cilia. Curr Biol 27:3430-3441.e6|
|Wang, Juan; Barr, Maureen M (2016) Ciliary Extracellular Vesicles: Txt Msg Organelles. Cell Mol Neurobiol 36:449-57|
|Lockhead, Dean; Schwarz, Erich M; O'Hagan, Robert et al. (2016) The tubulin repertoire of C. elegans sensory neurons and its context-dependent role in process outgrowth. Mol Biol Cell :|
|Maguire, Julie E; Silva, Malan; Nguyen, Ken C Q et al. (2015) Myristoylated CIL-7 regulates ciliary extracellular vesicle biogenesis. Mol Biol Cell 26:2823-32|
|Langenhan, Tobias; Barr, Maureen M; Bruchas, Michael R et al. (2015) Model Organisms in G Protein-Coupled Receptor Research. Mol Pharmacol 88:596-603|
|O'Hagan, Robert; Barr, Maureen M (2015) A motor relay on ciliary tracks. Nat Cell Biol 17:1517-9|
|Han, Ziduan; Boas, Stephanie; Schroeder, Nathan E (2015) Unexpected Variation in Neuroanatomy among Diverse Nematode Species. Front Neuroanat 9:162|
|Wang, Juan; Kaletsky, Rachel; Silva, Malan et al. (2015) Cell-Specific Transcriptional Profiling of Ciliated Sensory Neurons Reveals Regulators of Behavior and Extracellular Vesicle Biogenesis. Curr Biol 25:3232-8|
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