Fibroblast Growth Factor Signaling Regulates Neurogenesis at Multiple Stages in the Embryonic Olfactory Epithelium

Abstract

Lifelong neurogenesis in the mouse olfactory epithelium (OE) is regulated by the response of stem/progenitor cells to local signals, but embryonic and adult OE progenitors appear to be quite different—with potentially different mechanisms of regulation. A recently identified progenitor unique to embryonic OE—the nestin+ radial glial-like progenitor—precedes some Mash1+ progenitors in the olfactory receptor neuron (ORN) lineage, which then gives rise to immediate neuronal precursors and immature ORNs. Neurogenic drive at each stage is governed largely by exogenous factors. Fibroblast growth factor 2 (FGF2) is believed to increase cell proliferation in both presumptive OE stem cells and immediate neuronal precursors in explants, but whether FGF2 directly acts on different target progenitors or stages in the embryonic OE is not known. Here we show that fibroblast growth factor receptor (FGFR)1 and FGFR2 are found in a variety of embryonic olfactory cells, including olfactory ensheathing cells and their precursors, and neuronal nestin+ and Mash1+ progenitors. Combining gain and loss of function for FGF2 activity in a novel in vitro clonal progenitor assay, we reveal that different colony phenotypes are formed by presumably different OE progenitors. FGF2 is essential for the survival and expansion of colony-forming cells of the OE, and also enhances the proliferation of embryonic Mash1+ progenitors, leading to long-lived enhancement of neurogenesis. Our data suggest that distinct OE progenitors yield different in vitro phenotypes with different potentials, that colony-forming activity is profoundly altered by laminin and collagen, that multiple ORNs can be produced from single colony-forming progenitors, and demonstrate a broader progenitor range of FGF action in the embryonic OE than previously demonstrated.