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首页> 外文期刊>The Journal of Neuroscience: The Official Journal of the Society for Neuroscience >Presenilin 1 mutants impair the self-renewal and differentiation of adult murine subventricular zone-neuronal progenitors via cell-autonomous mechanisms involving notch signaling.
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Presenilin 1 mutants impair the self-renewal and differentiation of adult murine subventricular zone-neuronal progenitors via cell-autonomous mechanisms involving notch signaling.

机译：早老素1突变体通过涉及刻槽信号的细胞自主机制损害成年鼠脑室下区-神经元祖细胞的自我更新和分化。

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摘要

The vast majority of pedigrees with familial Alzheimer's disease (FAD) are caused by inheritance of mutations in the PSEN1 1 gene. While genetic ablation studies have revealed a role for presenilin 1 (PS1) in embryonic neurogenesis, little information has emerged regarding the potential effects of FAD-linked PS1 variants on proliferation, self-renewal and differentiation, key events that control cell fate commitment of adult brain neural progenitors (NPCs). We used adult brain subventricular zone (SVZ)-derived NPC cultures transduced with recombinant lentivirus as a means to investigate the effects of various PS1 mutants on self-renewal and differentiation properties. We now show that viral expression of several PS1 mutants in NPCs leads to impaired self-renewal and altered differentiation toward neuronal lineage, in vitro. In line with these observations, diminished constitutive proliferation and steady-state SVZ progenitor pool size was observed in vivo in transgenic mice expressing the PS1DeltaE9 variant. Moreover, NPC cultures established from the SVZ of adult mice expressing PS1DeltaE9 exhibit reduced self-renewal capacity and premature exit toward neuronal fates. To these findings, we show that both the levels of endogenous Notch/CBF-1-transcriptional activity and transcripts encoding Notch target genes are diminished in SVZ NPCs expressing PS1DeltaE9. The deficits in self-renewal and multipotency are restored by expression of Notch1-ICD or a downstream target of the Notch pathway, Hes1. Hence, we argue that a partial reduction in PS-dependent gamma-secretase processing of the Notch, at least in part, accounts for the impairments observed in SVZ NPCs expressing the FAD-linked PS1DeltaE9 variant.
机译：绝大多数家族性阿尔茨海默氏病（FAD）的系谱是由PSEN1 1基因突变的遗传引起的。虽然基因消融研究已经显示早老素1（PS1）在胚胎神经发生中的作用，但关于FAD关联的PS1变体对增殖，自我更新和分化，控制成人细胞命运的关键事件的潜在影响的信息很少。脑神经祖细胞（NPC）。我们使用成人慢脑室带（SVZ​​）来源的重组慢病毒转导的NPC培养作为一种手段来研究各种PS1突变体对自我更新和分化特性的影响。我们现在显示，NPC中几个PS1突变体的病毒表达会导致自我更新受损和体外神经元谱系分化改变。与这些观察一致，在表达PS1DeltaE9变体的转基因小鼠体内观察到组成型增殖减少和稳态SVZ祖细胞大小。此外，从表达PS1DeltaE9的成年小鼠的SVZ建立的NPC培养物表现出降低的自我更新能力，并且过早地退出神经元命运。对于这些发现，我们表明内源性Notch / CBF-1转录活性水平和编码Notch靶基因的转录本在表达PS1DeltaE9的SVZ NPC中均降低。通过Notch1-ICD或Notch通路Hes1下游靶点的表达可以恢复自我更新和多能性的缺陷。因此，我们认为，Notch的PS依赖性γ-分泌酶加工的部分减少至少部分解释了在表达FAD连锁的PS1DeltaE9变体的SVZ NPC中观察到的损伤。

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