Feedback Regulation of Neurogenesis in the Mammalian Olfactory Epithelium: New Insights from Genetics and Systems Biology

The mouse olfactory epithelium (OE) is an ideal model system for identifying and characterizing the factors that regulate proliferation and differentiation of neurons from their stem and progenitor cells. In part, this is because the OE undergoes neurogenesis throughout life, and does so exuberantly in response to injury (Graziadei and Monti Graziadei 1978; Mackay-Sim and Kittel 1991; Calof et al. 2002). However, another advantage of great significance is the fact that numerous studies have given us a good idea of the cell types that give rise to olfactory receptor neurons (ORNs) (Cau et al. 1997; Calof et al. 2002; Kawauchi et al. 2004, ; Beites et al. 2005; see also Chapter 5). Thus, in the neuronal lineage of the OE, four cell stages have been identified, in vitro and in vivo: (1) -expressing stem cells, which reside in the basal compartment of the epithelium, are thought to commit to the ORN lineage via expression of the proneural gene, (2) -expressing early progenitor cells, which divide and may act as transit-amplifying cells (Gordon et al. 1995), in turn give rise to (3) late-stage transit-amplifying cells, also known as immediate neuronal precursors (INPs), which express a second proneural gene, (Wu et al. 2003). INPs give rise to daughter cells that undergo terminal differentiation into (4) postmitotic -expressing ORNs. Figure 10.1A shows schematics of both the OE neuronal lineage and the spatial distribution of these cells within the OE in vivo. As is common to many epithelia, differentiation in the OE proceeds in a basal-to-apical direction: dividing stem and progenitor cells lie atop the basal lamina, and multiple layers of differentiated ORNs lie above the progenitor cells layers. Since the OE is able to sustain de novo neurogenesis throughout life and to regenerate in response to injury (Graziadei and Monti Graziadei 1978; Calof et al. 2002), it must contain stem cells. Indeed, several groups have been interested in harvesting OE stem cells for their therapeutic potential (e.g., Zhang et al. 2004; Othman et al. 2005). However, when OE is isolated and cultured in serum-free medium, although it avidly generates neurons for one to two days (Calof and Chikaraishi 1989), it rapidly loses the ability to undergo neurogenesis unless other factors or feeder cells are added (DeHamer et al. 1994; Holcomb et al. 1995; Mumm et al. 1996; Shou et al. 2000). In other words, OE neuronal stem and transit-amplifying cells in isolation are prone to undergoing differentiative divisions over self-replicative divisions, resulting in rapid expiration of these cell populations in tissue culture. This observation has prompted numerous studies to search for the environmental cues that are important for sustaining stem and progenitor cell self-renewal and maintaining the neurogenic potential of the OE.