Regeneration of Sensory Hair Cells Requires Localized Interactions between the Notch and Wnt Pathways

In vertebrates, mechano-electrical transduction of sound is accomplished by sensory hair cells. Whereas mammalian hair cells are not replaced when lost, in fish they constantly renew and regenerate after injury. In vivo tracking and cell fate analyses of all dividing cells during lateral line hair cell regeneration revealed that support and hair cell progenitors localize to distinct tissue compartments. Importantly, we find that the balance between self-renewal and differentiation in these compartments is controlled by spatially restricted Notch signaling and its inhibition of Wnt-induced proliferation. The ability to simultaneously study and manipulate individual cell behaviors and multiple pathways in vivo transforms the lateral line into a powerful paradigm to mechanistically dissect sensory organ regeneration. The striking similarities to other vertebrate stem cell compartments uniquely place zebrafish to help elucidate why mammals possess such low capacity to regenerate hair cells. [Display omitted] •Single-cell, in vivo lineage tracing of sensory hair cell regeneration•Self-renewing and differentiating cell divisions occur in distinct compartments•Self-renewal requires Wnt signaling and is inhibited by Notch-induced dkk2•Notch but not Wnt signaling affects hair cell differentiation Sensory hair cells, which transduce sound, cannot be replaced in mammals but are continuously regenerated in the zebrafish lateral line. Using live imaging, Romero-Carvajal et al. show that quiescence, self-renewal, and differentiation of fish sensory hair cells occur in distinct organ compartments, regulated by localized Notch and Wnt signaling interactions.