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FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation

Nature Genetics volume 41, pages 1037–1042 (2009)Cite this article

Abstract

Dandy-Walker malformation (DWM), the most common human cerebellar malformation, has only one characterized associated locus1,2. Here we characterize a second DWM-linked locus on 6p25.3, showing that deletions or duplications encompassing FOXC1 are associated with cerebellar and posterior fossa malformations including cerebellar vermis hypoplasia (CVH), mega-cisterna magna (MCM) and DWM. Foxc1-null mice have embryonic abnormalities of the rhombic lip due to loss of mesenchyme-secreted signaling molecules with subsequent loss of Atoh1 expression in vermis. Foxc1 homozygous hypomorphs have CVH with medial fusion and foliation defects. Human FOXC1 heterozygous mutations are known to affect eye development, causing a spectrum of glaucoma-associated anomalies (Axenfeld-Rieger syndrome, ARS; MIM no. 601631). We report the first brain imaging data from humans with FOXC1 mutations and show that these individuals also have CVH. We conclude that alteration of FOXC1 function alone causes CVH and contributes to MCM and DWM. Our results highlight a previously unrecognized role for mesenchyme-neuroepithelium interactions in the mid-hindbrain during early embryogenesis.

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Figure 1: Physical map of the 6p25.3 DWM locus.
Figure 2: Brain images of affected individuals within the 6p25.3 cohort.
Figure 3: Morphological cerebellar phenotype of Foxc1−/− embryos.
Figure 4: Loss of Foxc1 from hindbrain mesenchyme disrupts rhombic lip–derived cerebellar cellular populations.
Figure 5: Cerebellar morphology of Foxc1hith/hith mice.

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Acknowledgements

We thank the affected individuals and their families for their participation; C. Beaulieu for assistance with MRI; T. Kume for providing Foxc1+/− mice; S. Pleasure and A. Peterson for Foxc1+/hith mice; H. Sing, H. Hang, R. Arkell, N. Miura, J. Belmont, Q. Ma, B. Hogan, W. Duan, J. Johnson, M.E. Hatten, R. Miller, E. Grove, M. German, T. Jessell and R. Hevner for providing mutant brains, in situ probes or antibodies; and M. Walter for helpful discussions. This work was supported by the following awards: an Autism Speaks predoctoral fellowship to K.A.A., Alberta Heritage for Medical Research and Canadian Institute for Health Research grants to O.J.L., US National Institutes of Health grants KO8-NS48174-01A to A.G.B., R01-NS050375 to W.B.D. and R01-NS050386 to K.J.M., and March of Dimes Birth Defects Foundation award 6-FYO7-334 to K.J.M.

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Authors and Affiliations

  1. Committee on Neurobiology, University of Chicago, Chicago, Illinois, USA

    Kimberly A Aldinger & Kathleen J Millen

  2. Departments of Ophthalmology and Medical Genetics, University of Alberta, Edmonton, Canada

    Ordan J Lehmann

  3. Division of Medical Genetics, Department of Pediatrics, Stanford University, Stanford, California, USA

    Louanne Hudgins

  4. Department of Human Genetics, University of Chicago, Chicago, Illinois, USA

    Victor V Chizhikov, William B Dobyns & Kathleen J Millen

  5. Department of Pediatrics, Division of Neurology and the Interdisciplinary Graduate Program in Genetics, University of Iowa, Iowa City, Iowa, USA

    Alexander G Bassuk

  6. Department of Clinical Genetics, The Children's Hospital at Westmead, Sydney, New South Wales, Australia

    Lesley C Ades

  7. Discipline of Paediatrics and Child Health, University of Sydney, Sydney, New South Wales, Australia

    Lesley C Ades

  8. Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

    Ian D Krantz

  9. Department of Neurology, University of Chicago, Chicago, Illinois, USA

    William B Dobyns & Kathleen J Millen

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Contributions

K.A.A. contributed to study design and performed most human and mouse studies and manuscript writing. O.J.L. provided brain scans for multiple individuals and contributed to data analysis and manuscript writing. V.V.C. contributed to mouse immunohistochemical studies. L.H., A.G.B. and L.C.A. provided key phenotype data on one or more individuals. I.D.K. provided much of the initial ideas and data used to start this project, as well as new phenotype data on one subject. W.B.D. contributed to the initial design of the study, patient ascertainment, clinical evaluation including interpretation of all brain scans, delineation of the phenotype and manuscript writing. K.J.M. designed the study, supervised the mouse studies and contributed to manuscript writing.

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Correspondence to Kathleen J Millen.

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Aldinger, K., Lehmann, O., Hudgins, L. et al. FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation. Nat Genet 41, 1037–1042 (2009). https://doi.org/10.1038/ng.422

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