The role of MAPK and AKT signaling during zebrafish olfactory epithelium regeneration

The zebrafish olfactory epithelium (OE) is a neuroepithelium that is able to re- generate neurons. The ability of the OE for neuron regeneration stems from the pres- ence of a dual progenitor system that persists to the adulthood and consists of globose basal cells (GBC) and horizontal basal cells (HBC). In this dual system, GBCs com- pensate for daily loss of neurons while HBCs are dormant but activated upon injury to regenerate neurons. Transcriptome profiling of the damaged OE revealed upregulation of the HB-EGF in an early phase of regeneration and suggested a regulatory role in OE regeneration. Pharmacological inhibition of HB-EGF signaling and its receptor EGFR in addition to exogenous stimulation of HB-EGF confirmed the regulation of regener- ation by HB-EGF:EGFR interaction. However, cell types regulated by the binding of HB-EGF to EGFR, and cellular signaling pathways that mediate its pro-regenerative effect needed further investigation. In this work, roles of MAPK/ERK and PI3K/AKT signaling pathways which are both well-established to regulate cell fates were studied in the context of OE regeneration. For this purpose, loss of function approaches with pharmacological inhibitors of these pathways were followed by investigating their activ- ity in regenerating OE through phosphorylated isoforms. These experiments revealed that MAPK/ERK signaling is the downstream effector of HBEGF:EGFR interaction in cells most likely to be HBCs and it is necessary for recovery of neurons. Despite the fact that PI3K/AKT pathway was also active in these cells, PI3K/AKT signaling was not found to be necessary for functional OE regeneration and it is proposed to stimulate cell cycle progression by promoting cellular growth.