Factors regulating neurogenesis and programmed cell death in mouse olfactory epithelium

To identify factors regulating neurogenesis and programmed cell death in mouse olfactory epithelium (OE), and to determine the mechanisms by which these factors act, we have studied mouse OE using two major experimental paradigms: tissue culture of embryonic OE and cell types isolated from it; and ablation of the olfactory bulb ('bulbectomy') of adult mice, a procedure that induces programmed cell death of olfactory receptor neurons (ORNS) and a subsequent surge of neurogenesis in the OE in vivo. Such experiments have been used to characterize the cellular stages in the ORN lineage, leading to the realization that there are at least two distinct stages of proliferating neuronal progenitor cells interposed between the ORN and the stem cell that ultimately gives rise to it. The identification of a number of different factors that act to regulate proliferation and survival of ORNs and progenitor cells suggests that these multiple cell stages may each serve as a control point at which neuron number in the OE is regulated. Our recent studies of neuronal colony-forming progenitors (putative stem cells) of the OE suggest that even these cells, at the earliest stage in the ORN lineage so far identified, are subject to such regulation: if colony-forming progenitors are cultured in the presence of a large excess of differentiated ORNs, then the production of new neurons by progenitors is dramatically inhibited. This result suggests that differentiated ORNs produce a signal that feeds back to inhibit neurogenesis by their own progenitors, and provides a possible explanation for the observation that ORN death, consequent to bulbectomy, results in increased neurogenesis in the OE in vivo: death of ORNs may release neuronal progenitor cells from this inhibitory signal, produced by the differentiated ORNs that lie near them in the OE. Our current experiments are directed toward identifying the molecular basis of this inhibitory signal, and the cellular mechanism(s) by which it acts.