Article

Leukemia inhibitory factor is a key signal for injury-induced neurogenesis in the adult mouse olfactory epithelium.

Unité Mixte de Recherche 5020 Centre National de la Recherche Scientifique, Université Lyon I, 69622 Villeurbanne, France.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 04/2003; 23(5):1792-803.
Source: PubMed

ABSTRACT The mammalian olfactory epithelium (OE) is composed of primary olfactory sensory neurons (OSNs) that are renewed throughout adulthood by local, restricted neuronal progenitor cells. The molecular signals that control this neurogenesis in vivo are unknown. Using olfactory bulb ablation (OBX) in adult mice to trigger synchronous mitotic stimulation of neuronal progenitors in the OE, we show the in vivo involvement of a cytokine in the cellular events leading to the regeneration of the OE. We find that, of many potential mitogenic signals, only leukemia inhibitory factor (LIF) is induced before the onset of neuronal progenitor proliferation. The rise in LIF mRNA expression peaks at 8 hr after OBX, and in situ RT-PCR and immunocytochemistry indicate that LIF is upregulated, in part, in the injured neurons themselves. This rise in LIF is necessary for injury-induced neurogenesis, as OBX in the LIF knock-out mouse fails to stimulate cell proliferation in the OE. Moreover, delivery of exogenous LIF to the intact adult OE using an adenoviral vector stimulates BrdU labeling in the apical OE. Taken together, these results suggest that injured OSNs release LIF as a stimulus to initiate their own replacement.

Download full-text

Full-text

Available from: Emmanuel Moyse, Mar 12, 2014
0 Followers
 · 
94 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Short-term incubation with pharmacologically relevant concentrations of morphine has been shown to transiently affect the metabolism and redox status of NG108-15 cells through δ-opioid receptor stimulation, but apparently did not provoke cell death. The present work tries to determine if incubation with morphine at longer time intervals (24 h) provokes apoptosis and/or necrosis, as it has been described in other cell lines. We have also checked the potential modulatory role of yohimbine on these effects, on the basis of the previously described interactions between this drug and opioid receptor ligands. Incubation with morphine 0.1 and 10 μM provoked the appearance of images compatible with apoptosis (bebbling, pyknotic cells with cytoplasmic and nuclear condensation) and necrosis (cells swollen with vacuolated cytoplasm lacking cell processes) that could be observed directly and/or after staining with methylene blue, crystal violet and propidium iodide/4',6-diamidino-2-phenylindole (IP/DAPI). Quantification of apoptosis by activation of caspases 3 and 7 and DNA fragmentation with the Tunel assay revealed a modest but significant increase after incubation with the two concentrations of morphine used. Co-incubation with 10 μM yohimbine prevented all these effects of the opioid. The results extend previous findings of a yohimbine-sensitive, neurotoxic effect of morphine on NG108-15 cells. Copyright © 2012 John Wiley & Sons, Ltd.
    Journal of Applied Toxicology 01/2014; 34(1). DOI:10.1002/jat.2817 · 3.17 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The olfactory epithelium (OE) is unusual for its remarkable regenerative capacity and sustained neurogenesis of olfactory receptor neurons (ORNs) throughout adult life. Regeneration of ORNs is accomplished by basal cells in the OE, including stem cells and progenitor cells. Although there is considerable knowledge about the roles of OE basal cells in ORN turnover, the molecular mechanism that regulates the proliferation and differentiation of adult OE basal cells is not fully understood. As intercellular signaling molecules, purines have been reported to meditate proliferation, differentiation and migration of many kinds of neural stem cells. However, it is still unclear whether ATP, which could be released by injured ORNs, plays a role in regulating neurogenesis in ORN turnover. RT-PCR and immunohistochemistry were used to detect the expression of ionotropic purinergic receptors-P2X receptors in adult mouse OE. By using the olfactory bulbectomy model and in vivo administration of P2X receptors antagonists, the function of P2X receptors in regulating the proliferation of OE progenitor cell was evaluated. We found that basal cells in the adult mouse OE express functional P2X receptors, and blocking the activities of P2X receptors can significantly inhibit the injury-induced proliferation of OE basal cells. Our research provides evidence in support of the hypothesis that purinergic signaling can serve as a paracrine signal in regulating the neurogenesis of OE in adult mouse.
    International journal of pediatric otorhinolaryngology 07/2010; 74(7):747-51. DOI:10.1016/j.ijporl.2010.03.030 · 1.32 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: For the mammalian olfactory epithelium to continually detect odorant, neuronal survival, apoptosis, and regeneration must be coordinated. Here, we showed that the proto-oncogene BCL6, which encodes a transcriptional repressor required for lymphocyte terminal differentiation, contributes to the survival of olfactory sensory neurons (OSNs). In the olfactory epithelia of the BCL6 null mutant mice, many OSNs were positive for both OMP and GAP43. The epithelium was relatively thinner, showing many apoptotic signals. These characters were phenotypically similar to those of the wild-type mice treated with nasal lectin irrigation, which acutely induces apoptosis of OSNs. Odorant receptors were expressed normally in the epithelia of the mutant mice, and their overall expression profile based on DNA microarray analyses was roughly similar to that of the apoptosis-induced olfactory epithelia of the wild-type mice. Experimental increase of BCL6 together with green fluorescent protein in OSNs using adenovirus-mediated gene transfer made the epifluorescence last longer than the control fluorescence without exogenous BCL6 after the nasal lectin irrigation, indicating that BCL6 made the infected neurons survive longer. We conclude that BCL6 plays an active role in the survival of OSNs as an anti-apoptotic factor and confers immature OSNs enough time to fully differentiate into mature ones.
    Developmental Neurobiology 05/2010; 70(6):424-35. DOI:10.1002/dneu.20786 · 4.19 Impact Factor