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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways.
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Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways.

机译:内源性神经营养蛋白通过不同的信号传导途径调节皮层祖细胞的存活和分化。

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Cultured embryonic cortical progenitor cells will mimic the temporal differentiation pattern observed in vivo, producing neurons first and then glia. Here, we investigated the role of two endogenously produced growth factors, the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 (NT-3), in the early progenitor-to-neuron transition. Cultured cortical progenitors express BDNF and NT-3, as well as their receptors TrkB (tyrosine kinase receptor B) and TrkC. Inhibition of these endogenously expressed neurotrophins using function-blocking antibodies resulted in a marked decrease in the survival of cortical progenitors, accompanied by decreased proliferation and inhibition of neurogenesis. Inhibition of neurotrophin function also suppressed the downstream Trk receptor signaling pathways, PI3-kinase (phosphatidyl inositol-3-kinase) and MEK-ERK (MAP kinase kinase-extracellular signal-regulated kinase), indicating the presence of autocrine-paracrine neurotrophin:Trk receptor signaling in these cells. Moreover, specific inhibition of these two Trk signaling pathways led to distinct biological effects; inhibition of PI3-kinase decreased progenitor cell survival, whereas inhibition of MEK selectively blocked the generation of neurons, with no effects on survival or proliferation. Thus, neurotrophins made by cortical progenitor cells themselves signal through the TrkB and TrkC receptors to mediate cortical progenitor cell survival and neurogenesis via two distinct downstream signaling pathways.
机译:培养的胚胎皮质祖细胞将模仿体内观察到的时间分化模式,首先产生神经元,然后产生神经胶质。在这里,我们调查了两个内源性生长因子,即神经营养蛋白脑源性神经营养因子和神经营养蛋白3(NT-3)在祖细胞到神经元的早期转变中的作用。培养的皮质祖细胞表达BDNF和NT-3,以及它们的受体TrkB(酪氨酸激酶受体B)和TrkC。使用功能阻断抗体对这些内源性表达的神经营养蛋白的抑制导致皮质祖细胞的存活率显着降低,并伴随着增殖减少和神经发生抑制。抑制神经营养蛋白功能也抑制了下游Trk受体信号通路,PI3激酶(磷脂酰肌醇3激酶)和MEK-ERK(MAP激酶激酶-细胞外信号调节激酶),表明存在自分泌-旁分泌神经营养蛋白:Trk。这些细胞中的受体信号传导。此外,对这两个Trk信号通路的特异性抑制导致不同的生物学效应。抑制PI3激酶降低了祖细胞的存活,而抑制MEK则选择性地阻断了神经元的生成,而对存活或增殖没有影响。因此,由皮质祖细胞自身制造的神经营养蛋白通过TrkB和TrkC受体发出信号,从而通过两个不同的下游信号传导途径介导皮质祖细胞的存活和神经发生。

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