The Atoh1-lineage gives rise to hair cells and supporting cells within the mammalian cochlea

The organ of Corti, located within the mammalian cochlea, contains a precise mosaic of hair cells (HC) and supporting cells (SC), the patterning of which is critical for auditory function. Progenitors of HCs and SCs are found in the same post-mitotic region of the cochlear duct during early stages of cochlear development, and both HCs and SCs are absent in mice lacking the transcription factor Atoh1. Based on existing data, Atoh1 is thought to be the earliest determinant of HC fate, and to have a cell-autonomous role in HC differentiation, but the lineage of Atoh1-positive cells within the cochlear duct remains unclear. To address this issue, we used an inducible Atoh1Cre⁎PR allele to permanently mark Atoh1-expressing cells at different developmental time points. We found that up to 30% of cells from the Atoh1-lineage develop as SCs, and that the number of Atoh1-positive SCs decreases both spatially and temporally in a pattern consistent with ongoing commitment. Modulation of Notch signaling, necessary for formation of the HC–SC mosaic, changes the percentage of cells from the Atoh1-lineage that develop as either HCs or SCs. The HC–SC ratio is also affected by morphogenesis of the cochlea, as inhibiting the outgrowth of the cochlear duct increases the number of Atoh1-lineage cells that develop as SCs. Our results demonstrate that the Atoh1-lineage is established early in cochlear development, but also show that expression of Atoh1 does not absolutely result in commitment to a HC fate.

► Atoh1 is expressed in both hair and supporting cell precursors of the cochlea.
► Activation of Notch signaling inhibits Atoh1 expression and inhibits hair cell fate.
► Inhibition of cochlear outgrowth results in changes in cell fate.
► ATOH1 protein is down-regulated prior to Atoh1 mRNA in developing hair cells.