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Murine Joubert syndrome reveals Hedgehog signaling defects as a potential therapeutic target for nephronophthisis

Lookup NU author(s): Dr Ann Marie Hynes, Dr Shalabh Srivastava, Dr Lorraine Eley, Dr Marina Danilenko, Professor Peter Thelwall, Professor Nicholas Simmons, Dr Colin Miles, Professor John SayerORCiD



This is the authors' accepted manuscript of an article that has been published in its final definitive form by National Academy of Sciences , 2014.

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Nephronophthisis (NPHP) is the major cause of pediatric renal failure, yet the disease remains poorly understood, partly due to the lack of appropriate animal models. Joubert syndrome (JBTS) is an inherited ciliopathy giving rise to NPHP with cerebellar vermis aplasia and retinal degeneration. Among patients with JBTS and a cerebello-oculo-renal phenotype, mutations in CEP290 (NPHP6) are the most common genetic lesion. We present a Cep290 gene trap mouse model of JBTS that displays the kidney, eye, and brain abnormalities that define the syndrome. Mutant mice present with cystic kidney disease as neonates. Newborn kidneys contain normal amounts of lymphoid enhancer-binding factor 1 (Lef1) and transcription factor 1 (Tcf1) protein, indicating normal function of the Wnt signaling pathway; however, an increase in the protein Gli3 repressor reveals abnormal Hedgehog (Hh) signaling evident in newborn kidneys. Collecting duct cells from mutant mice have abnormal primary cilia and are unable to form spheroid structures in vitro. Treatment of mutant cells with the Hh agonist purmorphamine restored normal spheroid formation. Renal epithelial cells from a JBTS patient with CEP290 mutations showed similar impairments to spheroid formation that could also be partially rescued by exogenous stimulation of Hh signaling. These data implicate abnormal Hh signaling as the cause of NPHP and suggest that Hh agonists may be exploited therapeutically.

Publication metadata

Author(s): Hynes AM, Giles RH, Srivastava S, Eley L, Whitehead J, Danilenko M, Raman S, Slaats GG, Colville JG, Ajzenberg H, Kroes HY, Thelwall PE, Simmons NL, Miles CG, Sayer JA

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences of the United States of America

Year: 2014

Volume: 111

Issue: 27

Pages: 9893-9898

Online publication date: 08/07/2014

Acceptance date: 28/05/2014

Date deposited: 12/08/2014

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences


DOI: 10.1073/pnas.1322373111

PubMed id: 24946806


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Funder referenceFunder name
Anna-Liise Farquharson Kidney Cancer Research Fund, Princess Margaret Foundation
Kids Kidney Research
Northern Counties Kidney Research Fund
241955European Union/Framework Programme
CP11.18Dutch Kidney Fundation "Kouncil" Consortium