Dlx5 and Dlx6 homeobox genes are required for specification of the mammalian vestibular apparatus

The mammalian inner ear is a complex organ that develops from a surface ectoderm into distinct auditory and vestibular components. Congenital malformation of these two components resulting from single or multiple gene defects is a common clinical occurrence and is observed in patients with split hand/split foot malformation, a malformation which is phenocopied by D1x516 null mice. Analysis of mice lacking D1x5 and D1x6 homeobox genes identified their restricted and combined expression in the otic epithelium as a crucial regulator of vestibular cell fates. Otic induction initiates without incident in D1x5/6(-/-) embryos, but dorsal otic derivatives including the semicircular ducts, utricle, saccule, and endolymphatic duct fail to form. D1x5 and D1x6 seem to influence vestibular cell fates by restricting Pax2 and activating Gbx2 and Bmp4 expression domains. Given their proximity to the disease locus and the observed phenotype in D1x5/6 null mice, D1x5/6 are likely candidates to mediate the inner ear defects observed in patients with split hand/split foot malformation.