Defective Wnt-dependent Cerebellar Midline Fusion in a Mouse Model of Joubert Syndrome

Nat Med. 2011 Jun;17(6):726-31. doi: 10.1038/nm.2380. Epub 2011 May 29.

Abstract

The ciliopathy Joubert syndrome is marked by cerebellar vermis hypoplasia, a phenotype for which the pathogenic mechanism is unclear. To investigate Joubert syndrome pathogenesis, we have examined mice with mutated Ahi1, the first identified Joubert syndrome-associated gene. These mice show cerebellar hypoplasia with a vermis-midline fusion defect early in development. This defect is concomitant with expansion of the roof plate and is also evident in a mouse mutant for another Joubert syndrome-associated gene, Cep290. Furthermore, fetal magnetic resonance imaging (MRI) of human subjects with Joubert syndrome reveals a similar midline cleft, suggesting parallel pathogenic mechanisms. Previous evidence has suggested a role for Jouberin (Jbn), the protein encoded by Ahi1, in canonical Wnt signaling. Consistent with this, we found decreased Wnt reporter activity at the site of hemisphere fusion in the developing cerebellum of Ahi1-mutant mice. This decrease was accompanied by reduced proliferation at the site of fusion. Finally, treatment with lithium, a Wnt pathway agonist, partially rescued this phenotype. Our findings implicate a defect in Wnt signaling in the cerebellar midline phenotype seen in Joubert syndrome that can be overcome with Wnt stimulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple
  • Adaptor Proteins, Vesicular Transport
  • Animals
  • Cerebellar Diseases / etiology
  • Cerebellar Diseases / genetics
  • Cerebellar Diseases / pathology
  • Cerebellum / abnormalities*
  • Cerebellum / growth & development
  • Cerebellum / pathology
  • Cerebellum / physiology
  • Disease Models, Animal*
  • Eye Abnormalities / etiology
  • Eye Abnormalities / genetics
  • Eye Abnormalities / pathology
  • Humans
  • Kidney Diseases, Cystic / etiology
  • Kidney Diseases, Cystic / genetics
  • Kidney Diseases, Cystic / pathology
  • Lithium / pharmacology
  • Magnetic Resonance Imaging
  • Mice
  • Mice, Mutant Strains
  • Nuclear Proteins / genetics
  • Nuclear Proteins / physiology
  • Phenotype
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / physiology
  • Retina / abnormalities
  • Retina / pathology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Wnt Proteins / genetics
  • Wnt Proteins / physiology*

Substances

  • Adaptor Proteins, Vesicular Transport
  • Ahi1 protein, mouse
  • Cep290 protein, mouse
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Wnt Proteins
  • Lithium

Supplementary concepts

  • Agenesis of Cerebellar Vermis