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.
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