Deregulated FGF and homeotic gene expression underlies cerebellar vermis hypoplasia in CHARGE syndrome

Tian Yu, Linda C. Meiners, Katrin Danielsen, Monica T. Y. Wong, Timothy Bowler, Danny Reinberg, Peter J. Scambler, Conny M. A. van Ravenswaaij-Arts, M. Albert Basson*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    39 Citations (Scopus)
    197 Downloads (Pure)

    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.

    Original languageEnglish
    Article number01305
    Number of pages15
    JournaleLife
    Volume2
    DOIs
    Publication statusPublished - 24-Dec-2013

    Keywords

    • OTX2 EXPRESSION
    • MID/HINDBRAIN ORGANIZER
    • ANTERIOR NEUROECTODERM
    • NERVOUS-SYSTEM
    • INNER-EAR
    • HINDBRAIN
    • CHD7
    • GBX2
    • MIDBRAIN
    • MUTATIONS

    Cite this