Spatiotemporal transcriptomic analyses reveal molecular gradient patterning during development and the tonotopic organization along cochlear axis

The cochlea is a highly specialized organ, responsible for auditory functions, yet its development, spatial molecular profiles, and structural basis for hearing function remain poorly understood due to its structural complexity and intricate organization of various cell types. Disruption of cochlear architecture and development process can lead to cochlear malfunction, resulting in hearing defects, including frequency discrimination impairments and hearing loss. In this study, we present the first comprehensive spatiotemporal single-cell atlas of the cochlea, unveiling dynamic gene expression patterns and cellular patterning during development and adulthood. By integrating the spatial transcriptomics, normal single-cell transcriptomics, and RNA in situ detection, our analyses revealed distinct temporal gene expression profiles across the apical, middle, and basal regions of cochlea. Notably, spatial differential gene expression analyses uncovered regional heterogeneity among hair cell and spiral ganglion neuron subtypes, including differences in cell composition, cell-cell interactions, spatial localization. These findings suggest a cellular and molecular basis for sound frequency discrimination and sensitivity gradients along cochlear axis. Our spatiotemporal analyzes of the mouse cochlea provides a valuable resource for inner ear developmental research and offers insights into the structural, cellular, and molecular mechanisms underlying the tonotopic organization in mammals, and how their disrupting can lead to hearing impairment.