STAT3, an intracellular mediator of the effects of CNTF and other neurotrophic cytokines, has a distinct cytoplasmic function in inhibiting microtubule depolymerization in axons of motoneurons.
BackgroundVascular endothelial growth factor (VEGF) is an endothelial cell mitogen that stimulates vasculogenesis. It has also been shown to act as a neurotrophic factor in vitro and in vivo. Deletion of the hypoxia response element of the promoter region of the gene encoding VEGF in mice causes a reduction in neural VEGF expression, and results in adult-onset motor neurone degeneration that resembles amyotrophic lateral sclerosis (ALS). Investigating the molecular pathways to neurodegeneration in the VEGFδ/δ mouse model of ALS may improve understanding of the mechanisms of motor neurone death in the human disease.ResultsMicroarray analysis was used to determine the transcriptional profile of laser captured spinal motor neurones of transgenic and wild-type littermates at 3 time points of disease. 324 genes were significantly differentially expressed in motor neurones of presymptomatic VEGFδ/δ mice, 382 at disease onset, and 689 at late stage disease. Massive transcriptional downregulation occurred with disease progression, associated with downregulation of genes involved in RNA processing at late stage disease. VEGFδ/δ mice showed reduction in expression, from symptom onset, of the cholesterol synthesis pathway, and genes involved in nervous system development, including axonogenesis, synapse formation, growth factor signalling pathways, cell adhesion and microtubule-based processes. These changes may reflect a reduced capacity of VEGFδ/δ mice for maintenance and remodelling of neuronal processes in the face of demands of neural plasticity. The findings are supported by the demonstration that in primary motor neurone cultures from VEGFδ/δ mice, axon outgrowth is significantly reduced compared to wild-type littermates.ConclusionsDownregulation of these genes involved in axon outgrowth and synapse formation in adult mice suggests a hitherto unrecognized role of VEGF in the maintenance of neuronal circuitry. Dysregulation of VEGF may lead to neurodegeneration through synaptic regression and dying-back axonopathy.
In sensory neurons heat is transduced by a subfamily of TRP channels sharing sequence homology with the capsaicin-sensitive vanilloid receptor subtype 1 (TRPV1), but differing in their thermal response thresholds. To identify a neuronal cell line endogenously expressing noxious heat-transducing ion channels, we examined F-11 cells, a hybridoma derived from rat dorsal root ganglia and mouse neuroblastoma. Using RT-PCR, transcripts homologous to TRPV2 and TRPV4, but not to TRPV1 or TRPV3, were found. We isolated a full-length cDNA of 2.4 kb coding for a 757-amino acid protein corresponding to mouse TRPV2, which was further characterized by immunocytochemistry and electrophysiology. Using the whole-cell patch-clamp technique, we observed a heat-evoked increase in outward and inward currents with a threshold of 51.6 ± 0.2°C. The current-voltage relationship stimulated by a temperature of 52°C was characterized by an outward rectification with a reversal potential close to –10 mV. Heat-evoked currents could be inhibited by ruthenium red. There was no activation by stimulation with capsaicin or 2-aminoethoxydiphenyl borate. Our results indicate that F-11 cells express functional noxious heat-sensitive TRPV2 channels. Thus, we propose that F-11 cells represent a valuable in vitro model to characterize the properties of TRPV2 in a native neuronal environment.
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