Abstract
Loss of sensory hair cells leads to deafness and balance deficiencies. In contrast to mammalian hair cells, zebrafish ear and lateral line hair cells regenerate from poorly characterized support cells. Equally ill-defined is the gene regulatory network underlying the progression of support cells to differentiated hair cells. scRNA-Seq of lateral line organs uncovered five different support cell types, including quiescent and activated stem cells. Ordering of support cells along a developmental trajectory identified self-renewing cells and genes required for hair cell differentiation. scRNA-Seq analyses of fgf3 mutants, in which hair cell regeneration is increased, demonstrates that Fgf and Notch signaling inhibit proliferation of support cells in parallel by inhibiting Wnt signaling. Our scRNA-Seq analyses set the foundation for mechanistic studies of sensory organ regeneration and is crucial for identifying factors to trigger hair cell production in mammals. The data is searchable and publicly accessible via a web-based interface.
Highlights
Non-mammalian vertebrates readily regenerate sensory hair cells during homeostasis and after injury, whereas in mammals hair cell loss leads to permanent hearing and vestibular loss (Bermingham-McDonogh and Rubel, 2003; Brignull et al, 2009; Corwin and Cotanche, 1988; Cruz et al, 2015; Ryals and Rubel, 1988)
The lateral line system is one of the few sensory organs where stem cell behaviors can be observed at the single cell level in vivo because the organs are located in the skin of the animal, are experimentally accessible and easy to image
These results led to the hypothesis that some support cell populations are involved in signaling to trigger regeneration, which we tested by scRNA-Seq analyses of fgf3 mutants that strikingly show increased proliferation and hair cell regeneration
Summary
Non-mammalian vertebrates readily regenerate sensory hair cells during homeostasis and after injury, whereas in mammals hair cell loss leads to permanent hearing and vestibular loss (Bermingham-McDonogh and Rubel, 2003; Brignull et al, 2009; Corwin and Cotanche, 1988; Cruz et al, 2015; Ryals and Rubel, 1988). We and others showed that the zebrafish lateral line system is a powerful in vivo model to study the cellular and molecular basis of hair cell regeneration (Kniss et al, 2016; Lush and Piotrowski, 2014b; Ma and Raible, 2009; Romero-Carvajal et al, 2015; Viader-Llargues et al, 2018). The lateral line system is one of the few sensory organs where stem cell behaviors can be observed at the single cell level in vivo because the organs are located in the skin of the animal, are experimentally accessible and easy to image. These properties make it an ideal system to
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