title: Murine Joubert syndrome reveals Hedgehog signaling defects as a potential therapeutic target for nephronophthisis.
abstract: 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.
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom;
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Hynes
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, 3508 GA, Utrecht, The Netherlands;
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Giles
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom;
authors.forename: Shalabh
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom;
authors.forename: Lorraine
authors.initials: L
authors.lastname: Eley
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Whitehead
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom;
authors.forename: Marina
authors.initials: M
authors.lastname: Danilenko
authors.affiliation: Histopathology Department, Royal Victoria Infirmary, Newcastle upon Tyne National Health Service Foundation Trust Hospitals, Newcastle upon Tyne NE1 4LP, United Kingdom;
authors.forename: Shreya
authors.initials: S
authors.lastname: Raman
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, 3508 GA, Utrecht, The Netherlands;
authors.forename: Gisela G
authors.initials: GG
authors.lastname: Slaats
authors.affiliation: Newcastle Magnetic Resonance Centre, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, United Kingdom;
authors.forename: John G
authors.initials: JG
authors.lastname: Colville
authors.affiliation: Department of Nephrology and Hypertension, University Medical Center Utrecht, 3508 GA, Utrecht, The Netherlands;
authors.forename: Henry
authors.initials: H
authors.lastname: Ajzenberg
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, 3508 AB, Utrecht, The Netherlands;
authors.forename: Hester Y
authors.initials: HY
authors.lastname: Kroes
authors.affiliation: Newcastle Magnetic Resonance Centre, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE4 5PL, United Kingdom;Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom; and.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Thelwall
authors.affiliation: Institute of Cell and Molecular Biosciences, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom.
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Simmons
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom; john.sayer@ncl.ac.uk colin.miles@ncl.ac.uk.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Miles
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom; john.sayer@ncl.ac.uk colin.miles@ncl.ac.uk.
authors.forename: John A
authors.initials: JA
authors.lastname: Sayer
mesh_terms: D000015:Abnormalities, Multiple; D000818:Animals; D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; D002526:Cerebellar Diseases / Q000378:metabolism*; D002531:Cerebellum / Q000002:abnormalities; D003598:Cytoskeletal Proteins; D005124:Eye Abnormalities / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D053823:Hedgehog Proteins / Q000378:metabolism*; D052177:Kidney Diseases, Cystic / Q000151:congenital* / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics; D012160:Retina / Q000002:abnormalities* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000951:Antigens, Neoplasm; D018797:Cell Cycle Proteins; C513600:Cep290 protein, mouse; D003598:Cytoskeletal Proteins; D053823:Hedgehog Proteins; D009687:Nuclear Proteins