Suppressor of cytokine signaling 3 limits protection of leukemia inhibitory factor receptor signaling against central demyelination

Enhancement of oligodendrocyte survival through activation of leukemia inhibitory factor receptor (LIFR) signaling is a candidate therapeutic strategy for demyelinating disease. However, in other cell types, LIFR signaling is under tight negative regulation by the intracellular protein suppressor of cytokine signaling 3 (SOCS3). We, therefore, postulated that deletion of the SOCS3 gene in oligodendrocytes would promote the beneficial effects of LIFR signaling in limiting demyelination. By studying wild-type and LIF-knockout mice, we established that SOCS3 expression by oligodendrocytes was induced by the demyelinative insult, that this induction depended on LIF, and that enclogenously produced LIF was likely to be a key determinant of the CNS response to oligodendrocyte loss. Compared with wild-type controls, oligo-dendrocyte-specific SOCS3 conditional-knockout mice displayed enhanced c-fos activation and exogenous LIF-induced phosphorylation of signal transducer and activator of transcription 3. Moreover, these SOCS3-deficient mice were protected against cupri-zone-induced oligodendrocyte loss relative to wild-type animals. These results indicate that modulation of SOCS3 expression could facilitate the endogenous response to CNS injury.

Implantation of a scaffold following bulbectomy induces laminar organization of regenerating olfactory axons

Primary olfactory axons expressing different odorant receptors are interspersed within the olfactory nerve. However, upon reaching the outer nerve fiber layer of the olfactory bulb they defasciculate, sort out, and refasciculate prior to targeting glomeruli in fixed topographic positions. While odorant receptors are crucial for the final targeting of axons to glomeruli, it is unclear what directs the formation of the nerve fiber and glomerular layers of the olfactory bulb. While the olfactory bulb itself may provide instructive cues for the development of these layers, it is also possible that the incoming axons may simply require the presence of a physical scaffold to establish the outer laminar cytoarchitecture. In order to begin to understand the underlying role of the olfactory bulb in development of the outer layers of the olfactory bulb, we physically ablated the olfactory bulbs in OMP-IRES-LacZ and P2-IRES-tau-LacZ neonatal mice and replaced them with artificial biological scaffolds molded into the shape of an olfactory bulb. Regenerating axons projected around the edge of the cranial cavity at the periphery of the artificial scaffold and were able to form an olfactory nerve fiber layer and, to some extent, a glomerular layer. Our results reveal that olfactory axons are able to form rudimentary cytoarchitectonic layers if they are provided with an appropriately shaped biological scaffold. Thus, the olfactory bulb does not appear to provide any tropic substance that either attracts regenerating olfactory axons into the cranial cavity or induces these axons to form a plexus around its outer surface. (c) 2006 Elsevier B.V. All rights reserved.

mu O-conotoxin MrVIB selectively blocks Na(v)1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits

The tetroclotoxin-resistant voltage-gated sodium channel (VGSC) Na(v)1.8 is expressed predominantly by damage-sensing primary afferent nerves and is important for the development and maintenance of persistent pain states. Here we demonstrate that mu O-conotoxin MrVIB from Conus marmoreus displays substantial selectivity for Na(v)1.8 and inhibits pain behavior in models of persistent pain. In rat sensory neurons, submicromolar concentrations of MrVIB blocked tetroclotoxin-resistant current characteristic of Na(v)1.8 but not Na(v)1.9 or tetroclotoxin-sensitive VGSC currents. MrVIB blocked human Nav1.8 expressed in Xenopus oocytes with selectivity at least 10-fold greater than other VGSCs. In neuropathic and chronic inflammatory pain models, allodynia and hyperalgesia were both reduced by intrathecal infusion of MrVIB (0.03-3 nmol), whereas motor side effects occurred only at 30-fold higher doses. In contrast, the nonselective VGSC blocker lignocaine displayed no selectivity for allodynia and hyperalgesia versus motor side effects. The actions of MrVIB reveal that VGSC antagonists displaying selectivity toward Na(v)1.8 can alleviate chronic pain behavior with a greater therapeutic index than nonselective antagonists.

The sorting behaviour of olfactory and vomeronasal axons during regeneration

In order to begin to understand how primary olfactory and vomeronasal organ (VNO) axons target specific regions of the olfactory bulb, we examined the sorting behaviour of these axons following neonatal unilateral olfactory bulbectomy. Bulbectomy induced widespread ipsilateral death of the primary olfactory and VNO neurons. After 4 weeks, many new sensory axons had re-grown into the cranial cavity and established a prominent plexus with evidence of dense tufts that were similar in gross appearance to glomeruli. Axons expressing the cell adhesion molecule OCAM, which normally innervate the ventrolateral and rostral halves of the main and accessory olfactory bulbs, respectively, sorted out and segregated from those axons not expressing this molecule within the plexus. In addition, VNO axons formed large discrete bundles that segregated from main olfactory axons within the plexus. Thus, VNO and primary olfactory axons as well as discrete subpopulations of both are able to sort out and remain segregated in the absence of the olfactory bulb. Sorting and convergence of axons therefore occur independently of the olfactory bulb and are probably attributable either to inherent properties of the axons themselves or to interactions between the axons and accompanying glial ensheathing cells.

Brain tumour stem cells

The dogma that the genesis of new cells is a negligible event in the adult mammalian brain has long influenced our perception and understanding of the origin and development of CNS tumours. The discovery that new neurons and glia are produced throughout life from neural stem cells provides new possibilities for the candidate cells of origin of CNS neoplasias. The emerging hypothesis is that alterations in the cellular and genetic mechanisms that control adult neurogenesis might contribute to brain tumorigenesis, thereby allowing the identification of new therapeutic strategies.