The ciliopathy Joubert syndrome is marked by cerebellar vermis hypoplasia, a phenotype for which the pathogenic mechanism is unclear1,2,3. To investigate Joubert syndrome pathogenesis, we have examined mice with mutated Ahi1, the first identified Joubert syndrome–associated gene4,5. 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, Cep2906,7. 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 signaling8. 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 agonist9, 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.
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We are grateful to members of the Gleeson lab for technical expertise and feedback and B. Hamilton, M. Hatten and A. Joyner for helpful discussions on cerebellar development. We also thank the study subjects and the UCSD Neuroscience Microscopy Core. We thank J.K. Lee and B. Zheng for help with the biotinylated dextran amine tracing assay. We are grateful to S. Piccolo (University of Padua) for the BATgal mice. We thank R.T. Moon (University of Washington) for the Super Topflash construct and P. Mellon (UCSD) for the β-galactosidase expression construct, as well as K. Willert (UCSD) for stably transfected L cells and the β-catenin expression plasmid. M.A.L. received support from the Bear Necessities Pediatric Cancer Foundation and US National Institutes of Health–National Institute of General Medical Sciences–funded UCSD Genetics Training Program (T32 GM08666). This work was supported by the US National Institutes of Health (grants P30NS047101, R01NS052455 and R01NS048453) and the Burroughs Wellcome Fund in Translational Research (J.G.G.). J.G.G. is an investigator with Howard Hughes Medical Institute.
J.G.G. consults for Novartis in the area of ciliopathy therapeutics.
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Lancaster, M., Gopal, D., Kim, J. et al. Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome. Nat Med 17, 726–731 (2011). https://doi.org/10.1038/nm.2380
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