The transcription factor SIX1, and its cofactor EYA1, regulate inner ear development in vertebrates. Loss-of-function mutations in Six1/Eya1 cause developmental differences in craniofacial structures and the kidney, along with arrested ear formation in humans and mice. However, several human patients have the same symptoms without Six1/Eya1 mutations, indicating that other, unknown, genes may be involved. Here, Andrea Streit and colleagues find new downstream targets of the Six1 gene that coincide with human deafness loci in inner ear progenitors, revealing potential causative genes for human deafness-related syndromes. First, the authors identify 166 SIX1 target genes that are enriched in chick ear progenitors and are associated with enhancers that harbour SIX1 binding motifs. Four of these genes are further investigated and found to be regulated by SIX1 through direct or indirect mechanisms in both chick and frog during early ear development. Orthologues of the chick Six1 targets are conserved in human ear progenitors and 36 of these genes overlap with known deafness loci, of which some are related to the WNT signalling pathway that is crucial in ear development. Collectively, this study uncovers new mechanisms about SIX1 function in the vertebrate inner ear and candidates for human congenital deafness.
