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

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.