SOX2-dependent enhancer activation couples epithelial identity to neuronal maintenance

Abstract

The cochlear sensory epithelium and the spiral ganglion neurons it supports arise from a common pool of otic progenitors, yet the neurons remain dependent on the epithelium for guidance and survival long after the two lineages diverge. How that dependency is sustained as the progenitor pool generates increasingly restricted cell types is unknown. Here we show that SOX2 maintains this regulatory continuity. Deletion of Sox2 from the cochlear epithelium after cochlear neurogenesis does not affect neuroblast generation, delamination and proliferation; however, peripheral axons failed to reach the epithelium and neurons were progressively lost, identifying a non-cell-autonomous requirement for epithelial SOX2. Transcriptomic profiling revealed a SOX2-dependent epithelial programme enriched for neurotrophic and axon-guidance genes, including Ntf3 and Bdnf. In cochlear organoids, acute Sox2 deletion reduced H3K27ac at regulatory elements while H3K4me1 remained stable, consistent with SOX2 maintaining the activity of previously marked enhancers. Ntf3 and Bdnf exemplified distinct regulatory trajectories. At Ntf3, SOX2 occupied an enhancer whose activity depended on Sox2, whereas at Bdnf it occupied promoter-proximal elements in progenitors before ATOH1 engaged these and a hair-cell-active distal enhancer. Thus, SOX2 links sensory fate specification to epithelial-neuronal communication. More generally, our findings suggest that regulatory competence can persist through lineage restriction, while changing transcription-factor inputs partition its output among descendants to coordinate their development.