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

Victor V Chizhikov; Ian D Krantz; Kimberly A Aldinger; Louanne Hudgins; William B Dobyns; Kathleen J Millen; Ordan J Lehmann; Alexander G Bassuk; Lesley C Ades

doi:10.1038/ng.422

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

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

Victor V Chizhikov, Ian D Krantz, Kimberly A Aldinger, Louanne Hudgins, William B Dobyns, Kathleen J Millen, Ordan J Lehmann, Alexander G Bassuk and Lesley C Ades

Nature genetics, Vol.41(9), pp.1037-1042

09/2009

DOI: 10.1038/ng.422

PMCID: PMC2843139

PMID: 19668217

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Abstract

Dandy-Walker malformation (DWM), the most common human cerebellar malformation, has only one characterized associated locus. 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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Title: Subtitle: FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation
Creators: Victor V Chizhikov - Department of Human Genetics, University of Chicago
Ian D Krantz - Division of Human Genetics, The Children's Hospital of Philadelphia
Kimberly A Aldinger - Committee on Neurobiology, University of Chicago
Louanne Hudgins - Division of Medical Genetics, Department of Pediatrics, Stanford University
William B Dobyns - Department of Human Genetics, University of Chicago Department of Neurology, University of Chicago
Kathleen J Millen - Committee on Neurobiology, University of Chicago Department of Human Genetics, University of Chicago Department of Neurology, University of Chicago
Ordan J Lehmann - Departments of Ophthalmology and Medical Genetics, University of Alberta
Alexander G Bassuk - Department of Pediatrics, Division of Neurology and the Interdisciplinary Graduate Program in Genetics, University of Iowa
Lesley C Ades - Department of Clinical Genetics, The Children's Hospital at Westmead Discipline of Paediatrics and Child Health, University of Sydney
Resource Type: Journal article
Publication Details: Nature genetics, Vol.41(9), pp.1037-1042
DOI: 10.1038/ng.422
PMID: 19668217
PMCID: PMC2843139
NLM abbreviation: Nat Genet
ISSN: 1061-4036
eISSN: 1546-1718
Language: English
Date published: 09/2009
Academic Unit: Neurology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
Record Identifier: 9984013117002771

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