SOX10 restricts the formation of ectopic sensory patches in the postnatal mouse cochlea

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During the development of the mammalian cochlea, Notch signaling induces prosensory cell formation and later directs the differentiation of prosensory progenitor cells into hair cells and supporting cells. Previous studies have demonstrated that ectopic activation of Notch signaling in the early embryonic cochlea results in the formation of ectopic sensory patches in non-sensory regions; however, the ability to respond to Notch signaling declines with age and is lost after embryonic day (E) 13.5. Here, we observed that Notch activation at birth induced ectopic sensory patches in the mouse cochlea. These ectopic patches produced hair cell-like cells that express some proteins found in mature hair cells. Ectopic sensory patches result from hyperplasia of non-sensory cells throughout the cochlear duct that reentered the cell cycle and produced foci of prosensory competent cells. Within the organ of Corti, cells remained quiescent, however, cellular patterning was altered leading to differentiation of outer sulcus cells into supporting cell-like cells and altering the identity of pillar cells. We further investigated different levels of activated Notch signaling using a doxycycline-inducible system and found that the competence of the neonatal cochlea to induce prosensory markers, such as Sox2, correlates with the level of Notch activation, whereby higher levels of Notch signaling induced ectopic Sox2 expression. Because this conflicted with previous reports, we investigated the mechanism underlying prosensory reactivation in our experiments and found that the loss of one copy of Sox10 resulting from our use of Sox10 rtTA/+ knock-in mice facilitated prosensory competence, and that higher levels of Notch activation increased the penetrance of the phenotype. Our results demonstrate that the interaction between Notch signaling and SOX10 is important for the regulation of cellular identity in the developing inner ear.

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