Early radial positional information in the cochlea is optimized by a precise linear BMP gradient and enhanced by SOX2

Abstract

Positional information encoded in signaling molecules is essential for early patterning in the prosensory domain of the developing cochlea. The sensory epithelium, the organ of Corti, contains an exquisite repeating pattern of 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 up to the medial ~ 75% of the PSD from the pSMAD1/5/9 peak in the lateral edge 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. Furthermore, this is unique to the cochlear epithelium as the pSMAD1/5/9 gradient is exponential in the surrounding mesenchyme. 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. Last, through joint decoding maps of pSMAD1/5/9 and SOX2, we see that there is a high-fidelity mapping between signaling activity and position in the regions that will become Kölliker’s organ and the organ of Corti. Mapping is ambiguous in the prosensory domain precursory to the outer sulcus. Altogether, this research provides new insights into the precision of early morphogenetic patterning cues in the radial cochlea prosensory domain.

Sensory progenitors influence patterning of the mammalian auditory sensory epithelium

“…Previous studies quantitatively showed that the SOX2 domain that was once located on the medial edge on E12.5 was gradually repositioned to the center of the cochlear duct floor by E14.5 (Thompson et al, 2023). It is during this stage a prominent pool of progenitors are established in the IS domain where PORCN expression is enriched and adjacent to the SOX2positive cells in the sensory domain (Oliver et al, 2021).…”

“…Consistent with PORCN expression on E14.5, Mybl2 encoded a transcription factor that was also found to be expressed on the medial side of the cochlea, where PORCN enrichment was the highest. MYBL2 is most known for its role in regulating the cell cycle during development and disease (Liu et al, 2022b;Musa et al, 2017;Papetti and Augenlicht, 2011;Ward et al, 2018).…”

“…Our recent studies showed that the SOX2-positive sensory domain undergoes refinement to be repositioned from the medial edge on E12.5 to the center of the cochlear duct floor by E14.5 (Thompson et al, 2023). The SOX2-positive sensory domain will continue to form the sensory epithelium.…”