期刊
HUMAN MOLECULAR GENETICS
卷 18, 期 24, 页码 4711-4723出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddp434
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资金
- Institut National de la Sante et de la Recherche Me dicale (INSERM)
- Ministere de l'Education Nationale de la Recherche et de la Technologie (MRT)
- Fondation pour la Recherche Medicale (FRM) [DEQ20071210558]
- Association pour l'Utilisation du Rein Artificiel (AURA)
- Agence National de la Recherche (ANR) [R07089KS]
- Fulbright grant
- Centre National de la Recherche Scientifique (CNRS)
- French National Agency (ANR Crumbs)
- 'Equipe labellise e par la Ligue Nationale contre le Cancer'
- Universite Paris Descartes
Nephronophthisis (NPH) is an autosomal recessive disorder characterized by renal fibrosis, tubular basement membrane disruption and corticomedullary cyst formation leading to end-stage renal failure. The disease is caused by mutations in NPHP1-9 genes, which encode the nephrocystins, proteins localized to cell-cell junctions and centrosome/primary cilia. Here, we show that nephrocystin mRNA expression is dramatically increased during cell polarization, and shRNA-mediated knockdown of either NPHP1 or NPHP4 in MDCK cells resulted in delayed tight junction (TJ) formation, abnormal cilia formation and disorganized multi-lumen structures when grown in a three-dimensional collagen matrix. Some of these phenotypes are similar to those reported for cells depleted of the TJ proteins PALS1 or Par3, and interestingly, we demonstrate a physical interaction between these nephrocystins and PALS1 as well as their partners PATJ and Par6 and show their partial co-localization in human renal tubules. Taken together, these results demonstrate that the nephrocystins play an essential role in epithelial cell organization, suggesting a plausible mechanism by which the in vivo histopathologic features of NPH might develop.
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