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.