ABSTRACT
Olfactory Neurogenesis in Vivo .............................................................................245 10.3 Regulation of Neurogenesis by Negative Feedback ............................................................ 247
10.3.1 Neuronal Cell-Derived Factors Inhibit Progenitor Cell Proliferation in Vitro .............................................................................................. 247 10.3.2 Autoregulation of Neurogenesis by GDF11 ........................................................... 247 10.3.3 Follistatin (FST), a GDF11 Antagonist, Provides a Permissive
Environment for Neurogenesis ..............................................................................248 10.4 Computational Approaches Suggest Crucial Roles for
Negative Feedback in Achieving Rapid and Accurate Regeneration in the Olfactory Epithelium (OE) ........................................................................................250 10.4.1 GDF11 Controls the Ratio of Proliferative vs. Differentiative Divisions
of Immediate Neuronal Precursor Cells ................................................................250 10.4.2 Multiple Feedback Loops Improve Performance .................................................. 251 10.4.3 Follistatin (FST) Expression Creates a Stem Cell Niche in the Olfactory Epithelium (OE) .......................................................................... 253 10.4.4 Consequences of Feedback for Understanding Stem vs. Transit-Amplifying Cells ....................................................................................... 253
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, 2005; 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) Sox2-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, Mash1. (2) Mash1-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, Ngn1 (Wu et al. 2003). INPs give rise to daughter cells that undergo terminal differentiation into (4) postmitotic Ncam-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.
