The mammalian auditory system is comprised of the outer, middle and inner ears, and is responsible for both hearing and balance. Homeobox Six genes are expressed in many tissues throughout mammalian organogenesis, but their role in auditory system development is not well understood. Zheng et al., reporting in Development, have investigated the expression of Six1 during mammalian inner ear development and the role of this gene in auditory system development.

Inner ear development begins with the invagination of the otic placode to form the otic vesicle and subsequent structures of the inner ear. In normal mice, Six1 is expressed in all the sensory regions of the inner ear. Heterozygous Six1+/− mice showed some hearing loss, with internal examination of the auditory system revealing abnormalities in the middle ear. Homozygous Six1−/− mice lacked all sensory organ formation in the outer, middle and inner ears.

Six1 regulates cell proliferation during early otic development, as revealed from examination of the otic vesicles in Six1−/− mice. Despite the absence of apparent morphological differences in Six1−/− and wild-type mice, closer examination revealed numerous apoptotic cells in the wall of the Six1−/− otic vesicle. It therefore seems likely that Six1 regulates cell number during early otic development.

Zheng et al. went on to examine the interactions between Six1 and other signalling factors that have previously been established in early otic development. They found that the expression of Eya1, Pax2 and Pax8 were unaffected in Six1−/− otic vesicles. However, Six1 was required for Fgf3 expression and the maintenance of Fgf10, Bmp4, Nkx5.1 and Gata3 in the otic vesicle. So, Six1 is not required for the initiation of inner ear development, but is crucial for the regulation of signalling factors that are involved in cell-fate specification in the inner ear.

Further studies are needed to establish the complete molecular picture of how Six1 regulates the patterning of the inner ear.