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Defective Wnt-dependent cerebellar midline fusion in a mouse model of Joubert syndrome

Nature Medicine volume 17, pages 726–731 (2011)Cite this article

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Abstract

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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Figure 1: Reduced cerebellum size and foliation defects in Ahi1−/− mice.
Figure 2: Early proliferation defect and the absence of a postnatal Shh defect.
Figure 3: Midline fusion defect in mice and humans with Joubert syndrome.
Figure 4: Defective Wnt signaling and lithium rescue in Ahi1 mutant cerebella.

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Acknowledgements

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.

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  1. Madeline A Lancaster

    Present address: Current address: Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna, Austria.,

Authors and Affiliations

  1. Department of Pediatrics and Neurosciences, Laboratory for Neurogenetics, Howard Hughes Medical Institutes, Institute for Genomic Medicine, University of California, San Diego (UCSD), San Diego, California, USA

    Madeline A Lancaster, Dipika J Gopal, Joon Kim, Jennifer L Silhavy, Carrie M Louie, Bryan E Thacker, Yuko Williams & Joseph G Gleeson

  2. Radiology Department, Kasr Al-Ainy Hospital, Cairo University, Cairo, Egypt

    Sahar N Saleem

  3. Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt

    Maha S Zaki

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  1. Madeline A Lancaster
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Contributions

J.G.G. and M.A.L. conceived of and designed the experimental approach, interpreted data and wrote the manuscript. M.A.L. and D.J.G. carried out in vivo characterization experiments. M.A.L. performed in vitro Wnt assays. J.K. and Y.W. designed and generated Cep290-mutant mice. S.N.S. and M.S.Z. performed human diagnoses and provided MRIs. J.L.S. generated constructs and materials for in vitro assays. C.M.L. and B.E.T. contributed to in vivo characterizations. J.G.G. directed and supervised the project.

Corresponding author

Correspondence to Joseph G Gleeson.

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Competing interests

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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