The roles of Irx3 and Irx5 in mammalian inner ear development

Abstract

Iroquois genes encode a family of transcription factors containing TALE class homeodomain. They are regarded as prepatterning genes in Drosophila sensory organ development. There are six members (Irx1Irx6) of Iroquois genes in mouse and human. Irx3 and Irx5 are linked genes on mouse chromosome 8, which are involved in many mammalian developmental processes. However, the roles of Irx3 and Irx5 in mammalian hearing loss are poorly understood. To identify the function of these two genes in inner ear development, we have investigated two reporter knock‐in mouse mutants: Irx3lacZ, Irx5EGFP, and a double knock‐out mutant: Irx3/5‐/‐. Irx3 and Irx5 have overlapping expression domains in the developing inner ear. Physiological tests indicated that the Irx3lacZ and Irx5EGFP mutant mice displayed hearing defect, while Irx3/5‐/‐ mice were embryonic lethal. Although paint filling analysis showed the normal cochlea morphology of Irx3lacZ and Irx5EGFP mutant mice, ectopic inner hair cells have been discovered in the organ of Corti. Interestingly, the cochlear duct of Irx3/5‐/‐ mice was enlarged and shortened, and the basal part of the cochlea was fused with the saccule. There were also numerous vestibular‐like ectopic hair cells surrounded by ectopic Sox2‐positive cells in the greater epithelial ridge of cochlea. The organ of Corti was malformed with neither hair cell differentiation nor supporting cell differentiation at E16.5. In summary, our results indicate that Irx3 and Irx5 cooperatively pattern the boundary between the vestibule and the cochlea and they are important for the cochlear sensory neural cell specification.