Cellular and molecular analysis of regenerative neurogenesis in the zebrafish (Danio rerio) olfactory epithelium

Abstract

The olfactory epithelium (OE) has a high regenerative capacity that ensures the lifelong replacement of olfactory sensory neurons (OSNs). Different modes of neurogen esis originate from the selective activity of two distinct stem cell populations in the OE. In mammals, maintenance and regenerative neurogenesis are attributed to the selective activity of globose basal (GBC) and horizontal basal cells (HBC), respectively. How ever, the identity and function of similar progenitor cells in the OE of non-mammalian vertebrates remain elusive. This study demonstrates that a dual progenitor cell sys tem also exists in the zebrafish OE but with distinctive features when compared to mammalian models. HBC-like cells reside within the basal layer along the sensory OE, while GBC-like cells are confined to two isolated regions flanking the sensory OE. The positional and functional differences between these progenitor populations establish a balance between constitutive and regenerative modes of neurogenesis in the OE. Here, OE regeneration in response to global and OSN-specific injuries is examined in detail. The OE launches a rapid regenerative response upon chemical lesion, which results in HBC-like cell activation and OSN regeneration within the sensory OE. However, in response to selective OSN ablation, accelerated OSN regeneration is characteristically seen around the OE margins similar to the neurogenic activity in the intact OE. This crucial finding suggests that different injury conditions may affect HBC- and GBC-like cells selectively. RNA-sequencing analysis of the regenerating OE suggests that the diffusible signaling factor HB-EGF may have a critical role at the onset of regenerative neurogenesis. Exogenous HB-EGF administration induces OSN regeneration, while pharmacological inhibition of HB-EGF activity suppresses the regenerative response.