Nephronophthisis is an autosomal recessive kidney disease and the most common genetic cause of end-stage renal disease in children and young adults. Nephronophthisis is caused by mutation in one of at least five genes, NPHP1 - NPHP5. NPHP, autosomal dominant polycystic kidney disease (ADPKD) and other human cystic kidney diseases have been associated with defects in cilia. The NPHP protein products (the nephrocystins) localize to cilia, but almost nothing is known about the cellular and molecular functions of these important proteins. The nematode Caenorhabditis elegans offers significant experimental advantages for characterizing the physiological roles of the nephrocystins in their native cellular environments. We have developed and established the worm as a model for NPHP. We showed that nphp-1 and nphp-4 are expressed in ciliated sensory nervous system and are coexpressed with the C. elegans ADPKD genes lov-1/PC-1 and pkd-2/PC-2. Similar to the human nephrocystins, GFP-tagged NPHP-1 and NPHP-4 proteins localize to cilia. Consistent with a role in sensation, we found that nphp-1 and nphp-4 deletion mutants form cilia but are defective in several sensory behaviors, including male mating and dauer formation. We propose and will test three models for nephrocystin function. In the first model, the nephrocystins play a structural role and regulate cilia development or morphogenesis. In the second model, the nephrocystins function in ciliary protein transport. In the final model, the nephrocystins act in a signaling capacity to mediate sensory transduction within or from the cilium. The high level of species conservation of ciliary-localized NPHP and ADPKD proteins makes it likely that these studies in C. elegans will help elucidate how the nephrocystins work in the human kidney in normal and pathological disease states. The results of this proposal will provide valuable insight into several areas, including the functions of the nephrocystins, protein transport, sensory signaling transduction, and human ciliary diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK074746-01
Application #
7083809
Study Section
Cellular and Molecular Biology of the Kidney Study Section (CMBK)
Program Officer
Rasooly, Rebekah S
Project Start
2006-05-01
Project End
2009-04-30
Budget Start
2006-05-01
Budget End
2007-04-30
Support Year
1
Fiscal Year
2006
Total Cost
$212,692
Indirect Cost
Name
University of Wisconsin Madison
Department
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
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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
O'Hagan, Robert; Barr, Maureen M (2015) A motor relay on ciliary tracks. Nat Cell Biol 17:1517-9
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
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; Wang, Juan; Barr, Maureen M (2014) Mating behavior, male sensory cilia, and polycystins in Caenorhabditis elegans. Semin Cell Dev Biol 33:25-33
Warburton-Pitt, Simon R F; Silva, Malan; Nguyen, Ken C Q et al. (2014) The nphp-2 and arl-13 genetic modules interact to regulate ciliogenesis and ciliary microtubule patterning in C. elegans. PLoS Genet 10:e1004866
Barr, Maureen M (2014) C. elegans male mating behavior. Introduction. Semin Cell Dev Biol 33:1-2

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