Abstract
The olfactory epithelium (OE) of the mouse provides a unique system for understanding how cell birth and cell death interact to regulate neuron number during development and regeneration. We have examined cell death in the OE in normal adult mice; in adult mice subjected to unilateral olfactory bulbectomy (surgical removal of one olfactory bulb, the synaptic target of olfactory receptor neurons (ORNs) of the OE); and in primary cell cultures derived from embryonic mouse OE.In vivo,cells at all stages in the neuronal lineage—proliferating neuronal precursors, immature ORNs, and mature ORNs—displayed signs of apoptotic cell death; nonneuronal cells did not. Bulbectomy dramatically increased the number of apoptotic cells in the OE on the bulbectomized side. Shortly following bulbectomy, increased cell death involved neuronal cells of all stages. Later, cell death remained persistently elevated, but this was due to increased apoptosis by mature ORNs alone.In vitro,apoptotic death of both ORNs and their precursors could be inhibited by agents that prevent apoptosis in other cells: aurintricarboxylic acid (ATA), a membrane-permeant analog of cyclic AMP (CPT-cAMP), and certain members of the neurotrophin family of growth factors (brain-derived neurotrophic factor, neurotrophin 3, and neurotrophin 5), although no neurotrophin was as effective at promoting survival as ATA or CPT-cAMP. Consistent with observed effects of neurotrophins, immunohistochemistry localized the neurotrophin receptors trkB and trkC to fractions of ORNs scattered throughout neonatal OE. These results suggest that apoptosis may regulate neuronal number in the OE at multiple stages in the neuronal lineage and that multiple factors—potentially including certain neurotrophins—may be involved in this process.
Highlights
During vertebrate development, over half of the neurons in some areas of the nervous system die (Oppenheim, 1991)
The TUNEL technique (DNA end-labeling with deoxynucleotide terminal transferase and dUTP-biotin (Gavrieli et al, 1992)) was used to test for DNA fragmentation in the mouse olfactory epithelium (OE) following unilateral bulbectomy
In order to assess the timecourse and extent of cell death in the OE following disruption of contact with the OB, sections of OE from animals sacrificed at timepoints from 12 hr to 12 weeks following bulbectomy were processed for TUNEL staining
Summary
Over half of the neurons in some areas of the nervous system die (Oppenheim, 1991). Occurring neuronal death is thought to result from limitations in availability of trophic factors necessary for neuronal survival Such factors appear to suppress an endogenous genetic program, known as programmed cell death or apoptosis (Oppenheim, 1991; Johnson and Deckwerth, 1993). The fraction of a population of mature neurons that dies under these conditions often differs substantially from the fraction that dies during development: It varies widely depending on the type of neuron, and it is strongly dependent on both the age of the animal and the distance of the lesion from the neuronal cell body (Snider et al, 1992) It is not yet clear whether injury-induced neuronal death results from a loss of trophic factors derived from synaptic target tissue or whether apoptosis is the predominant mechanism by which such cells die. The data suggest that different factors may be responsible for regulating apoptosis at these different developmental stages
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