title: Deregulated FGF and homeotic gene expression underlies cerebellar vermis hypoplasia in CHARGE syndrome.
abstract: Mutations in CHD7 are the major cause of CHARGE syndrome, an autosomal dominant disorder with an estimated prevalence of 1/15,000. We have little understanding of the disruptions in the developmental programme that underpin brain defects associated with this syndrome. Using mouse models, we show that Chd7 haploinsufficiency results in reduced Fgf8 expression in the isthmus organiser (IsO), an embryonic signalling centre that directs early cerebellar development. Consistent with this observation, Chd7 and Fgf8 loss-of-function alleles interact during cerebellar development. CHD7 associates with Otx2 and Gbx2 regulatory elements and altered expression of these homeobox genes implicates CHD7 in the maintenance of cerebellar identity during embryogenesis. Finally, we report cerebellar vermis hypoplasia in 35% of CHARGE syndrome patients with a proven CHD7 mutation. These observations provide key insights into the molecular aetiology of cerebellar defects in CHARGE syndrome and link reduced FGF signalling to cerebellar vermis hypoplasia in a human syndrome. DOI: http://dx.doi.org/10.7554/eLife.01305.001.
authors.affiliation: Department of Craniofacial Development and Stem Cell Biology, King's College London, London, United Kingdom.
authors.forename: Tian
authors.initials: T
authors.lastname: Yu
authors.forename: Linda C
authors.initials: LC
authors.lastname: Meiners
authors.forename: Katrin
authors.initials: K
authors.lastname: Danielsen
authors.forename: Monica Ty
authors.initials: MT
authors.lastname: Wong
authors.forename: Timothy
authors.initials: T
authors.lastname: Bowler
authors.forename: Danny
authors.initials: D
authors.lastname: Reinberg
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
authors.forename: Conny Ma
authors.initials: CM
authors.lastname: van Ravenswaaij-Arts
authors.forename: M Albert
authors.initials: MA
authors.lastname: Basson
mesh_terms: D000818:Animals; D058747:CHARGE Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D065814:Cerebellar Vermis / Q000002:abnormalities / Q000378:metabolism*; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D051524:Fibroblast Growth Factor 8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D005838:Genotype; D057895:Haploinsufficiency; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D009154:Mutation; D051857:Otx Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype
chemical_list: C507367:Chd7 protein, mouse; D004268:DNA-Binding Proteins; C496457:Fgf8 protein, mouse; C513182:Gbx2 protein, mouse; D018398:Homeodomain Proteins; D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D051524:Fibroblast Growth Factor 8; D004265:DNA Helicases; C491434:CHD7 protein, human
keywords: CHARGE syndrome; CHD7; FGF8; GBX2; OTX2; cerebellum