Early precision of radial patterning of the mouse cochlea is achieved by a linear BMP signaling gradient and is further refined by SOX2

Abstract

Positional information encoded in signaling molecules is essential for early patterning in the prosensory domain of the developing cochlea. The cochlea contains an exquisite repeating pattern of sensory hair cells and supporting cells. This requires precision in the morphogen signals that set the initial radial compartment boundaries, but this has not been investigated. To measure gradient formation and morphogenetic precision in developing cochlea, we developed a quantitative image analysis procedure measuring SOX2 and pSMAD1/5/9 profiles in mouse embryos at embryonic day (E)12.5, E13.5, and E14.5. Intriguingly, we found that the pSMAD1/5/9 profile forms a linear gradient in the medial ~75% of the PSD during E12.5 and E13.5. This is a surprising activity readout for a diffusive BMP4 ligand secreted from a tightly constrained lateral region since morphogens typically form exponential or power-law gradient shapes. This is meaningful for gradient interpretation because while linear profiles offer the theoretically highest information content and distributed precision for patterning, a linear morphogen gradient has not yet been observed. In addition to the information-optimized linear profile, we found that while pSMAD1/5/9 is stable during this timeframe, an accompanying gradient of SOX2 shifts dynamically. Third, we see through joint decoding maps of pSMAD1/5/9 and SOX2 that there is a high-didelity mapping between signaling activity and position in the regions soon to become Kolliker's organ and the organ of Corti, where radial patterns are more intricate than lateral regions. Mapping is ambiguous in the prosensory domain precursory to the outer sulcus, where cell fates are uniform. Altogether, this research provides new insights into the precision of early morphogenetic patterning cues in the radial cochlea prosensory domain.