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Nedd9 restrains renal cystogenesis in Pkd1⁻/⁻ mice

Author:
Nikonova, Anna S., Plotnikova, Olga V., Serzhanova, Victoria, Efimov, Andrey, Bogush, Igor, Cai, Kathy Q., Hensley, Harvey H., Egleston, Brian L., Klein-Szanto, Andres, Seeger-Nukpezah, Tamina, Golemis, Erica A.
Source:
Proceedings of the National Academy of Sciences of the United States of America 2014 v.111 no.35 pp. 12859-12864
ISSN:
0027-8424
Subject:
alleles, animal models, autosomal dominant polycystic kidney disease, calcium, cilia, genotype, humans, mice, mutants, mutation, neoplasms, pathogenesis, people, phenotype, renal function, resorption, scaffolding proteins, signal transduction
Abstract:
Mutations inactivating the cilia-localized Pkd1 protein result in autosomal dominant polycystic kidney disease (ADPKD), a serious inherited syndrome affecting ∼1 in 500 people, in which accumulation of renal cysts eventually destroys kidney function. Severity of ADPKD varies throughout the population, for reasons thought to involve differences both in intragenic Pkd1 mutations and in modifier alleles. The scaffolding protein NEDD9, commonly dysregulated during cancer progression, interacts with Aurora-A (AURKA) kinase to control ciliary resorption, and with Src and other partners to influence proliferative signaling pathways often activated in ADPKD. We here demonstrate Nedd9 expression is deregulated in human ADPKD and a mouse ADPKD model. Although genetic ablation of Nedd9 does not independently influence cystogenesis, constitutive absence of Nedd9 strongly promotes cyst formation in the tamoxifen-inducible Pkd1fl/fl;Cre/Esr1 ⁺ mouse model of ADPKD. This cystogenic effect is associated with striking morphological defects in the cilia of Pkd1 ⁻/⁻;Nedd9 ⁻/⁻ mice, associated with specific loss of ciliary localization of adenylase cyclase III in the doubly mutant genotype. Ciliary phenotypes imply a failure of Aurora-A activation: Compatible with this idea, Pkd1 ⁻/⁻;Nedd9 ⁻/⁻ mice had ciliary resorption defects, and treatment of Pkd1 ⁻/⁻ mice with a clinical Aurora-A kinase inhibitor exacerbated cystogenesis. In addition, activation of the ADPKD-associated signaling effectors Src, Erk, and the mTOR effector S6 was enhanced, and Ca ²⁺ response to external stimuli was reduced, in Pkd1 ⁻/⁻;Nedd9 ⁻/⁻ versus Pkd1 ⁻/⁻ mice. Together, these results indicated an important modifier action of Nedd9 on ADPKD pathogenesis involving failure to activate Aurora-A.
Agid:
1787064