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.
|Original language||English (US)|
|Number of pages||6|
|State||Published - Sep 2009|
Bibliographical noteFunding Information:
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.