Neural stem cells proliferate and maintain multipotency when cultured in the presence of FGF2, but subsequent lineage commitment by the cells is nevertheless influenced by the exposure to FGF2. Here we show that FGF2 effects on neural stem cells are mediated, in part, by beta-catenin. Conversely, the effects of beta-catenin in neural stem cells depend in part upon whether there is concurrent fibroblast growth factor (FGF) signaling. FGF2 increases beta-catenin signaling through several different mechanisms including increased expression of beta-catenin mRNA, increased nuclear translocation of beta-catenin, increased phosphorylation of GSK-3beta, and tyrosine phosphorylation of beta-catenin. Overexpression of beta-catenin in the presence of FGF2 helps to maintain neural progenitor cells in a proliferative state. However, overexpression of beta-catenin in the absence of FGF2 enhances neuronal differentiation. Further, chromatin immunoprecipitation (ChIP) assays demonstrate that both beta-catenin and Lef1 bind directly to the neurogenin promoter, and luciferase reporter assays demonstrate that beta-catenin is directly involved in the regulation of neurogenin 1 and possibly other proneural genes when neural stem cells are cultured in the presence of FGF2. We suggest that the balance between the mitogenic effects and the proneural effects of beta-catenin is determined by the presence of FGF signaling.
Although Sox1, Sox2, and Sox3 are all part of the Sox-B1 group of transcriptional regulators, only Sox1 appears to play a direct role in neural cell fate determination and differentiation. We find that overexpression of Sox1 but not Sox2 or Sox3 in cultured neural progenitor cells is sufficient to induce neuronal lineage commitment. Sox1 binds directly to the Hes1 promoter and suppresses Hes1 transcription, thus attenuating Notch signaling. Sox1 also binds to beta-catenin and suppresses beta-catenin-mediated TCF/LEF signaling, thus potentially attenuating the wnt signaling pathway. The C-terminus of Sox1 is required for both of these interactions. Sox1 also promotes exit of cells from cell cycle and up-regulates transcription of the proneural bHLH transcription factor neurogenin 1 (ngn1). These observations suggest that Sox1 works through multiple independent pathways to promote neuronal cell fate determination and differentiation.
Furious and paralytic rabies differ in clinical manifestations and survival periods. The authors studied magnetic resonance imaging (MRI) and cytokine and virus distribution in rabies-infected dogs of both clinical types. MRI examination of the brain and upper spinal cord was performed in two furious and two paralytic dogs during the early clinical stage. Rabies viral nucleoprotein RNA and 18 cytokine mRNAs at 12 different brain regions were studied. Rabies viral RNA was examined in four furious and four paralytic dogs during the early stage, and in one each during the late stage. Cytokine mRNAs were examined in two furious and two paralytic dogs during the early stage and in one each during the late stage. Larger quantities of rabies viral RNA were found in the brains of furious than in paralytic dogs. Interleukin-1beta and interferon-gamma mRNAs were found exclusively in the brains of paralytic dogs during the early stage. Abnormal hypersignal T2 changes were found at hippocampus, hypothalamus, brainstem, and spinal cord of paralytic dogs. More widespread changes of less intensity were seen in furious dog brains. During the late stage of infection, brains from furious and paralytic rabid dogs were similarly infected and there were less detectable cytokine mRNAs. These results suggest that the early stage of furious dog rabies is characterized by a moderate inflammation (as indicated by MRI lesions and brain cytokine detection) and a severe virus neuroinvasiveness. Paralytic rabies is characterized by delayed viral neuroinvasion and a more intense inflammation than furious rabies. Dogs may be a good model for study of the host inflammatory responses that may modulate rabies virus neuroinvasiveness.
Neuronal activities play critical roles in both neurogenesis and neural regeneration. In that sense, electrically conductive and biocompatible biomaterial scaffolds can be applied in various applications of neural tissue engineering. In this study, we fabricated a novel biomaterial for neural tissue engineering applications by coating electrospun poly(lactic acid) (PLA) nanofibers with a conducting polymer, polypyrole (PPy), via admicellar polymerization. Optimal conditions for polymerization and preparation of PPy-coated electrospun PLA nanofibers were obtained by comparing results from scanning electron microscopy, X-ray photoelectron spectrometer, and surface conductivity tests. In vitro cell culture experiments showed that PPy-coated electrospun PLA fibrous scaffold is not toxic. The scaffold could support attachment and migration of neural progenitor cells. Neurons derived from progenitor exhibited long neurite outgrowth under electrical stimulation. Our study concluded that PPy-coated electrospun PLA fibers had a good biocompatibility with neural progenitor cells and may serve as a promising material for controlling progenitor cell behaviors and enhancing neural repair.
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