HB-EGF promotes progenitor cell proliferation and sensory neuron regeneration in the zebrafish olfactory epithelium

Abstract

Maintenance and regeneration of the zebrafish olfactory epithelium (OE) are supported by two distinct progenitor cell populations that occupy spatially discrete stem cell niches and respond to different tissue conditions. Globose basal cells (GBCs) reside at the inner and peripheral margins of the sensory OE and are constitutively active to replace sporadically dying olfactory sensory neurons (OSNs). In contrast, horizontal basal cells (HBCs) are uniformly distributed across the sensory tissue and are selectively activated by acute injury conditions. Here we show that expression of the heparin-binding epidermal growth factor-like growth factor (HB-EGF) is strongly and transiently upregulated in response to OE injury and signals through the EGF receptor (EGFR), which is expressed by HBCs. Exogenous stimulation of the OE with recombinant HB-EGF promotes HBC expansion and OSN neurogenesis in a pattern that resembles the tissue response to injury. In contrast, pharmacological inhibition of HB-EGF membrane shedding, HB-EGF availability, and EGFR signaling strongly attenuate or delay injury-induced HBC activity and OSN restoration without affecting maintenance neurogenesis by GBCs. Thus, HB-EGF/EGFR signaling appears to be a critical component of the signaling network that controls HBC activity and, consequently, repair neurogenesis in the zebrafish OE.