The role of egfr and jak/stat signaling during regenerative neurogenesis in the zebrafish olfactory epithelium

The zebrafish olfactory epithelium (OE) has an exceptional neurogenic capacity, which supports the continuous replacement of olfactory sensory neurons (OSNs) and efficient regeneration after injury. These processes depend on the presence of a dual stem cell system that is comprised of globose (GBCs) and horizontal basal cells (HBCs), which selectively contribute to maintenance of the intact and repair of the injured OE, respectively. Transcriptome profiling revealed strong upregulation of the HB-EGF. Exogenous stimulation and pharmacological inhibition of HB-EGF signaling show a selective effect on HBCs, suggesting HB-EGF is a key signal for OE regeneration. Among the cell surface receptors for HB-EGF, only the transcript levels of ErbB1/EGFR are upregulated in response to injury. EGFR expression localizes to HBCs, suggesting that HB-EGF signals through EGFR to activate in injury-responsive HBCs. To investigate the roles of EGFR and JAK/STAT signaling on OSN neurogenesis, the effect of pharmacological inhibition of the pathways on maintenance and repair neurogenesis were evaluated. Inhibition of EGFR signaling resulted in the suppression of basal proliferative activity, which, however, only slightly reduced the rate of OSNs turnover in the intact OE. In the injured tissue, on the other hand, EGFR inhibition resulted in a dramatic impairment of OSN regeneration by preventing the induction of HBC proliferation. A similar impairment in OSN regeneration could also be observed when JAK/STAT signaling was inhibited. Tissue analysis of JAK/STAT activation pointed to an injury-responsive population that is distinct from HBCs. These results suggest that both EGFR and JAK/STAT signaling are necessary for repair neurogenesis but that they are active in distinct populations of the OSN lineage.