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

Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9893-8. doi: 10.1073/pnas.1322373111. Epub 2014 Jun 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple
  • Animals
  • Antigens, Neoplasm
  • Cell Cycle Proteins
  • Cerebellar Diseases / metabolism*
  • Cerebellum / abnormalities
  • Cytoskeletal Proteins
  • Eye Abnormalities / metabolism*
  • Fluorescent Antibody Technique
  • Hedgehog Proteins / metabolism*
  • Kidney Diseases, Cystic / congenital*
  • Kidney Diseases, Cystic / metabolism
  • Kidney Diseases, Cystic / therapy
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Proteins / genetics
  • Retina / abnormalities*
  • Retina / metabolism
  • Signal Transduction*

Substances

  • Antigens, Neoplasm
  • Cell Cycle Proteins
  • Cep290 protein, mouse
  • Cytoskeletal Proteins
  • Hedgehog Proteins
  • Nuclear Proteins

Supplementary concepts

  • Agenesis of Cerebellar Vermis
  • Nephronophthisis, familial juvenile