Fig. 4.
Regulation of cellular differentiation along the cochlear basal-to-apical (tonotopic) axis. Patterning of the long, tonotopic, axis of the spiral cochlea occurs via several events, which occur in gradients along its basal-to-apical axis. The upper panel shows the spiraled cochlea, highlighting its association with the spiral ganglion. The middle panel illustrates the duct ‘unrolled’, with the narrow base representing the high frequency-responding end and the wider apex representing the low frequency-responding end. The lower panel depicts some of the events that occur during various stages of cochlear development. Cochlear prosensory cells exit the cell cycle (in response to CDKN1B expression) in a gradient that initiates in the apex and extends towards the base of the cochlear duct between E12 and E14. In contrast, cellular differentiation (marked by Atoh1 expression) begins near the base at E13 and extends to the apex by E16. As a result, cells in the apex of the cochlea are maintained in a post-mitotic but uncommitted state for approximately 4 days. Timing of the onset of differentiation is mediated, at least in part, through a base-to-apex gradient of downregulation of Lin28b/Hmga2. The gradient of differentiation, and potentially downregulation of Lin28b/Hmga2, is regulated through a temporal base-to-apex decrease in Shh signaling from adjacent spiral ganglion neurons (SGNs).