The peripheral olfactory system is able to recover after injury, i.e., the olfactory epithelium reconstitutes, the olfactory nerve regenerates, and the olfactory bulb is reinnervated, with a facility that is unique within the mammalian nervous system. Cell renewal in the epithelium is directed to replace neurons when they die in normal animals and does so at an accelerated pace after damage to the olfactory nerve. Neurogenesis persists because neuron-competent progenitor cells, including transit amplifying and immediate neuronal precursors, are maintained within the population of globose basal cells. Notwithstanding events in the neuron-depleted epithelium, the death of both non-neuronal cells and neurons directs multipotent globose basal cell progenitors, to give rise individually to sustentacular cells and horizontal basal cells as well as neurons. Multiple growth factors, including TGF-alpha, FGF2, BMPs, and TGF-betas, are likely to be central in regulating choice points in epitheliopoiesis. Reinnervation of the bulb is rapid and robust. When the nerve is left undisturbed, i.e., by lesioning the epithelium directly, the projection of the reconstituted epithelium onto the bulb is restored to near-normal with respect to rhinotopy and in the targeting of odorant receptor-defined neuronal classes to small clusters of glomeruli in the bulb. However, at its ultimate level, i.e., the convergence of axons expressing the same odorant receptor onto one or a few glomeruli, specificity is not restored unless a substantial number of fibers of the same type are spared. Rather, odorant receptor-defined subclasses of neurons innervate an excessive number of glomeruli in the rough vicinity of their original glomerular targets.

The loss of Fragile X mental retardation protein (FMRP) causes Fragile X syndrome, the most common inherited mental retardation and single gene cause of autism. Although postsynaptic functions for FMRP are well established, potential roles at the presynaptic apparatus remain largely unexplored. Here, we characterize the expression of FMRP and its homologs, FXR1P and FXR2P, in the developing, mature and regenerating rodent nervous system, with a focus on presynaptic expression. As expected, FMRP is expressed in the somatodendritic domain in virtually all neurons. However, FMRP is also localized in discrete granules (Fragile X granules; FXGs) in a subset of brain regions including frontal cortex, hippocampal area CA3 and olfactory bulb glomeruli. Immunoelectron microscopy shows that FMRP is localized at presynaptic terminals and in axons within these FXG-rich regions. With the exception of the olfactory bulb, FXGs are prominent only in the developing brain. Experiments in regenerating olfactory circuits indicate that peak FXG expression occurs 2-4 weeks after neurogenesis, a period that correlates with synapse formation and refinement. Virtually all FXGs contain FXR2P, while region-selective subsets harbor FMRP and/or FXR1P. Genetic studies show that FXR2P is essential for FXG expression, while FMRP regulates FXG number and developmental profile. These findings suggest that Fragile X proteins play a distinct, presynaptic role during discrete developmental epochs in defined circuits of the mammalian CNS. We propose that the neurological defects in Fragile X syndrome, including the autistic features, could be due in part to the loss of FMRP function in presynaptic compartments.

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The olfactory epithelium and its neuronal population are known to have a substantial capacity to recover after either direct injury or damage to the olfactory nerve. However, the mechanisms underlying that capacity for recovery, and indeed the limits on the recovery process, are not well understood. The aim of this study is to describe in detail the way in which the olfactory epithelium reconstitutes after direct injury. Adult male rats were exposed to 330 ppm methyl bromide (MeBr) gas for a single 6-hour period. The exposure destroys all of the neurons and sustentacular cells in over 95% of the olfactory epithelium of food-restricted rats and in over 90% of the epithelium in ad-libitum-fed rats of the same weight, yet substantial recovery of the olfactory epithelium occurs. In response to the lesion, cellular proliferation increases markedly beginning between 24 and 48 hours, peaks at 1 week, and persists at levels higher than the control level for more than 4 weeks after MeBr exposure. Even though proliferation accelerates promptly, the beginning of neuronal reconstitution is delayed; only a few immature neurons are observed 3 days after the lesion, yet they reappear in large numbers by the end of the first week. The first mature neurons emerge between 7 and 14 days after lesion and increase to near normal numbers by 4-6 weeks. In association with the restoration of the neuronal population, basal cell proliferation returns to control levels between 4 and 6 weeks after damage. Likewise, sustentacular cells, identifiable by anticytokeratin 18 labeling, reappear rapidly and reform a distinct lamina in the superficial aspect of the epithelium. They closely resemble their counterparts in control epithelium with regard to disposition and shape by 3 weeks after lesion and with regard to expression of olfactory-specific cytochrome P450s by 8 weeks. Thus, most areas of the epithelium are restored to a near normal appearance and cellular composition by the end of 8 weeks, suggesting that the MeBr paradigm for lesioning the epithelium offers significant advantages over techniques such as Triton X-100 or ZnSO4 irrigation. However, not all measures of epithelial status are normal even at 8 weeks. Immature neurons remain slightly more numerous than normal at this time. Furthermore, some areas of the olfactory epithelium do not recover after MeBr lesion and are replaced by respiratory epithelium.(ABSTRACT TRUNCATED AT 400 WORDS)

The capacity of the olfactory epithelium (OE) for lifelong neurogenesis and regeneration depends on the persistence of neurocompetent stem cells, which self-renew as well as generating all of the cell types found within the nasal epithelium. This Review focuses on the types of stem and progenitor cells in the epithelium and their regulation. Both horizontal basal cells (HBCs) and some among the population of globose basal cells (GBCs) are stem cells, but the two types plays vastly different roles. The GBC population includes the basal cells that proliferate in the uninjured OE and is heterogeneous with respect to transcription factor expression. From upstream in the hierarchy to downstream, GBCs encompass 1) Sox2+/Pax6+ stem-like cells that are totipotent and self-renew over the long term, 2) Ascl1+ transit-amplifying progenitors with a limited capacity for expansive proliferation, and 3) Neurog1+/NeuroD1+ immediate precursor cells that make neurons directly. In contrast, the normally quiescent HBCs are activated to multipotency and proliferate when sustentacular cells are killed, but not when only OSNs die, indicating that HBCs are reserve stem cells that respond to severe epithelial injury. The master regulator of HBC activation is the ΔN isoform of the transcription factor p63; eliminating ΔNp63 unleashes HBC multipotency. Notch signaling, via Jagged1 ligand on Sus cells and Notch1 and Notch2 receptors on HBCs, is likely to play a major role in setting the level of p63 expression. Thus, ΔNp63 becomes a potential therapeutic target for reversing the neurogenic exhaustion characteristic of the aged OE.