The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination

TLDR

During inner ear development, the sensory primordium of the cochlea is patterned into inner and outer hair cells separated by supporting cells, and Math1, a homolog of Drosophila atonal, is known to be necessary and sufficient for hair cell production. Our study shows that Math1 is not required to establish the postmitotic sensory primordium but is essential for selecting and differentiating hair cells within it, as Math1 expression appears only after primordium formation and its loss blocks hair cell generation while leaving the primordium intact, leading to apoptosis in a basal‑to‑apical gradient.

Abstract

During embryonic development of the inner ear, the sensory primordium that gives rise to the organ of Corti from within the cochlear epithelium is patterned into a stereotyped array of inner and outer sensory hair cells separated from each other by non-sensory supporting cells. Math1, a close homolog of the Drosophila proneural gene atonal, has been found to be both necessary and sufficient for the production of hair cells in the mouse inner ear. Our results indicate that Math1 is not required to establish the postmitotic sensory primordium from which the cells of the organ of Corti arise, but instead is limited to a role in the selection and/or differentiation of sensory hair cells from within the established primordium. This is based on the observation that Math1 is only expressed after the appearance of a zone of non-proliferating cells that delineates the sensory primordium within the cochlear anlage. The expression of Math1 is limited to a subpopulation of cells within the sensory primordium that appear to differentiate exclusively into hair cells as the sensory epithelium matures and elongates through a process that probably involves radial intercalation of cells. Furthermore, mutation of Math1 does not affect the establishment of this postmitotic sensory primordium, even though the subsequent generation of hair cells is blocked in these mutants. Finally, in Math1 mutant embryos, a subpopulation of the cells within the sensory epithelium undergo apoptosis in a temporal gradient similar to the basal-to-apical gradient of hair cell differentiation that occurs in the cochlea of wild-type animals.