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Abstract #24627 Published in IGR 11-4
FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation
Aldinger KA; Lehmann OJ; Hudgins L; Chizhikov VV; Bassuk AG; Ades LC; Krantz ID; Dobyns WB; Millen KJNature Genetics 2009; 41: 1037-1042
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.
K. J. Millen. Committee on Neurobiology, University of Chicago, Chicago, IL, United States. kmillen@genetics.bsd.uchicago.edu
Classification:
3.4.2 Gene studies (Part of: 3 Laboratory methods > 3.4 Molecular genetics)
9.1.3 Syndromes of Axenfeld, Rieger, Peters, aniridia (Part of: 9 Clinical forms of glaucomas > 9.1 Developmental glaucomas)
9.4.15 Glaucoma in relation to systemic disease (Part of: 9 Clinical forms of glaucomas > 9.4 Glaucomas associated with other ocular and systemic disorders)
