Abstract
The sox2 expressing (sox2+) progenitors in adult mammalian inner ear lose the capacity to regenerate while progenitors in the zebrafish lateral line are able to proliferate and regenerate damaged HCs throughout lifetime. To mimic the HC damage in mammals, we have established a zebrafish severe injury model to eliminate both progenitors and HCs. The atoh1a expressing (atoh1a+) HC precursors were the main population that survived post severe injury, and gained sox2 expression to initiate progenitor regeneration. In response to severe injury, yap was activated to upregulate lin28a transcription. Severe-injury-induced progenitor regeneration was disabled in lin28a or yap mutants. In contrary, overexpression of lin28a initiated the recovery of sox2+ progenitors. Mechanistically, microRNA let7 acted downstream of lin28a to activate Wnt pathway for promoting regeneration. Our findings that lin28a is necessary and sufficient to regenerate the exhausted sox2+ progenitors shed light on restoration of progenitors to initiate HC regeneration in mammals.
Highlights
The auditory epithelium is a delicate structure located in the cochlea that is composed of sensory hair cells (HCs) and nonsensory support cells (SCs)
Notch pathway from 3-day-post-fertilization to 5dpf, we found that SCs were exhausted by persistent differentiation into HCs (Figure 1—figure supplement 1)
The zebrafish lateral line provides a valuable model for studying the mechanism underpinning progenitor regeneration
Summary
The auditory epithelium is a delicate structure located in the cochlea that is composed of sensory hair cells (HCs) and nonsensory support cells (SCs). A subset of postmitotic progenitors start to express high levels of atoh and downregulate sox expression to differentiate into the HC precursors (Dabdoub et al, 2008; Zhong et al, 2019; Cai and Groves, 2015; Zhang et al, 2017). Afterwards, their terminal differentiation toward mature HCs is promoted by the upregulation of atoh target genes, such as pou4f3 (Cai et al, 2015). In the differentiating HCs secret Notch ligands to activate Notch pathway, which inhibits atoh expression in neighboring cells and forces them to adopt the SC fate (Abdolazimi et al, 2016; Costa et al, 2017; Lanford et al, 1999)
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